Visitor counter, Heat Map, Conversion tracking, Search Rank

  1. Mariana P Torrente, Edward Chuang, Megan M Noll, Meredith E Jackrel, Michelle S Go and James Shorter.
    Mechanistic Insights into Hsp104 Potentiation.. The Journal of biological chemistry 291(10):5101–15, March 2016.
    Abstract Potentiated variants of Hsp104, a protein disaggregase from yeast, can dissolve protein aggregates connected to neurodegenerative diseases such as Parkinson disease and amyotrophic lateral sclerosis. However, the mechanisms underlying Hsp104 potentiation remain incompletely defined. Here, we establish that 2-3 subunits of the Hsp104 hexamer must bear an A503V potentiating mutation to elicit enhanced disaggregase activity in the absence of Hsp70. We also define the ATPase and substrate-binding modalities needed for potentiated Hsp104(A503V) activity in vitro and in vivo. Hsp104(A503V) disaggregase activity is strongly inhibited by the Y257A mutation that disrupts substrate binding to the nucleotide-binding domain 1 (NBD1) pore loop and is abolished by the Y662A mutation that disrupts substrate binding to the NBD2 pore loop. Intriguingly, Hsp104(A503V) disaggregase activity responds to mixtures of ATP and adenosine 5'-($\gamma$-thio)-triphosphate (a slowly hydrolyzable ATP analogue) differently from Hsp104. Indeed, an altered pattern of ATP hydrolysis and altered allosteric signaling between NBD1 and NBD2 are likely critical for potentiation. Hsp104(A503V) variants bearing inactivating Walker A or Walker B mutations in both NBDs are inoperative. Unexpectedly, however, Hsp104(A503V) retains potentiated activity upon introduction of sensor-1 mutations that reduce ATP hydrolysis at NBD1 (T317A) or NBD2 (N728A). Hsp104(T317A/A503V) and Hsp104(A503V/N728A) rescue TDP-43 (TAR DNA-binding protein 43), FUS (fused in sarcoma), and $\alpha$-synuclein toxicity in yeast. Thus, Hsp104(A503V) displays a more robust activity that is unperturbed by sensor-1 mutations that greatly reduce Hsp104 activity in vivo. Indeed, ATPase activity at NBD1 or NBD2 is sufficient for Hsp104 potentiation. Our findings will empower design of ameliorated therapeutic disaggregases for various neurodegenerative diseases.
    URL, DOI BibTeX

    @article{Torrente2016,
    	abstract = "Potentiated variants of Hsp104, a protein disaggregase from yeast, can dissolve protein aggregates connected to neurodegenerative diseases such as Parkinson disease and amyotrophic lateral sclerosis. However, the mechanisms underlying Hsp104 potentiation remain incompletely defined. Here, we establish that 2-3 subunits of the Hsp104 hexamer must bear an A503V potentiating mutation to elicit enhanced disaggregase activity in the absence of Hsp70. We also define the ATPase and substrate-binding modalities needed for potentiated Hsp104(A503V) activity in vitro and in vivo. Hsp104(A503V) disaggregase activity is strongly inhibited by the Y257A mutation that disrupts substrate binding to the nucleotide-binding domain 1 (NBD1) pore loop and is abolished by the Y662A mutation that disrupts substrate binding to the NBD2 pore loop. Intriguingly, Hsp104(A503V) disaggregase activity responds to mixtures of ATP and adenosine 5'-($\gamma$-thio)-triphosphate (a slowly hydrolyzable ATP analogue) differently from Hsp104. Indeed, an altered pattern of ATP hydrolysis and altered allosteric signaling between NBD1 and NBD2 are likely critical for potentiation. Hsp104(A503V) variants bearing inactivating Walker A or Walker B mutations in both NBDs are inoperative. Unexpectedly, however, Hsp104(A503V) retains potentiated activity upon introduction of sensor-1 mutations that reduce ATP hydrolysis at NBD1 (T317A) or NBD2 (N728A). Hsp104(T317A/A503V) and Hsp104(A503V/N728A) rescue TDP-43 (TAR DNA-binding protein 43), FUS (fused in sarcoma), and $\alpha$-synuclein toxicity in yeast. Thus, Hsp104(A503V) displays a more robust activity that is unperturbed by sensor-1 mutations that greatly reduce Hsp104 activity in vivo. Indeed, ATPase activity at NBD1 or NBD2 is sufficient for Hsp104 potentiation. Our findings will empower design of ameliorated therapeutic disaggregases for various neurodegenerative diseases.",
    	author = "Torrente, Mariana P and Chuang, Edward and Noll, Megan M and Jackrel, Meredith E and Go, Michelle S and Shorter, James",
    	doi = "10.1074/jbc.M115.707976",
    	issn = "1083-351X",
    	journal = "The Journal of biological chemistry",
    	month = "mar",
    	number = 10,
    	pages = "5101--15",
    	pmid = 26747608,
    	title = "{Mechanistic Insights into Hsp104 Potentiation.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26747608",
    	volume = 291,
    	year = 2016
    }
    
  2. Korrie L Mack and James Shorter.
    Engineering and Evolution of Molecular Chaperones and Protein Disaggregases with Enhanced Activity.. Frontiers in molecular biosciences 3:8, January 2016.
    Abstract Cells have evolved a sophisticated proteostasis network to ensure that proteins acquire and retain their native structure and function. Critical components of this network include molecular chaperones and protein disaggregases, which function to prevent and reverse deleterious protein misfolding. Nevertheless, proteostasis networks have limits, which when exceeded can have fatal consequences as in various neurodegenerative disorders, including Parkinson's disease and amyotrophic lateral sclerosis. A promising strategy is to engineer proteostasis networks to counter challenges presented by specific diseases or specific proteins. Here, we review efforts to enhance the activity of individual molecular chaperones or protein disaggregases via engineering and directed evolution. Remarkably, enhanced global activity or altered substrate specificity of various molecular chaperones, including GroEL, Hsp70, ClpX, and Spy, can be achieved by minor changes in primary sequence and often a single missense mutation. Likewise, small changes in the primary sequence of Hsp104 yield potentiated protein disaggregases that reverse the aggregation and buffer toxicity of various neurodegenerative disease proteins, including $\alpha$-synuclein, TDP-43, and FUS. Collectively, these advances have revealed key mechanistic and functional insights into chaperone and disaggregase biology. They also suggest that enhanced chaperones and disaggregases could have important applications in treating human disease as well as in the purification of valuable proteins in the pharmaceutical sector.
    URL, DOI BibTeX

    @article{Mack2016,
    	abstract = "Cells have evolved a sophisticated proteostasis network to ensure that proteins acquire and retain their native structure and function. Critical components of this network include molecular chaperones and protein disaggregases, which function to prevent and reverse deleterious protein misfolding. Nevertheless, proteostasis networks have limits, which when exceeded can have fatal consequences as in various neurodegenerative disorders, including Parkinson's disease and amyotrophic lateral sclerosis. A promising strategy is to engineer proteostasis networks to counter challenges presented by specific diseases or specific proteins. Here, we review efforts to enhance the activity of individual molecular chaperones or protein disaggregases via engineering and directed evolution. Remarkably, enhanced global activity or altered substrate specificity of various molecular chaperones, including GroEL, Hsp70, ClpX, and Spy, can be achieved by minor changes in primary sequence and often a single missense mutation. Likewise, small changes in the primary sequence of Hsp104 yield potentiated protein disaggregases that reverse the aggregation and buffer toxicity of various neurodegenerative disease proteins, including $\alpha$-synuclein, TDP-43, and FUS. Collectively, these advances have revealed key mechanistic and functional insights into chaperone and disaggregase biology. They also suggest that enhanced chaperones and disaggregases could have important applications in treating human disease as well as in the purification of valuable proteins in the pharmaceutical sector.",
    	author = "Mack, Korrie L and Shorter, James",
    	doi = "10.3389/fmolb.2016.00008",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mack, Shorter - 2016 - Engineering and Evolution of Molecular Chaperones and Protein Disaggregases with Enhanced Activity.pdf:pdf",
    	issn = "2296-889X",
    	journal = "Frontiers in molecular biosciences",
    	month = "jan",
    	pages = 8,
    	pmid = 27014702,
    	title = "{Engineering and Evolution of Molecular Chaperones and Protein Disaggregases with Enhanced Activity.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4791398\&tool=pmcentrez\&rendertype=abstract",
    	volume = 3,
    	year = 2016
    }
    
  3. Meredith E Jackrel, Keolamau Yee, Amber Tariq, Annie I Chen and James Shorter.
    Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.. ACS chemical biology 10(12):2672–9, December 2015.
    Abstract Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or $\alpha$-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity.
    URL, DOI BibTeX

    @article{Jackrel2015a,
    	abstract = "Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or $\alpha$-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity.",
    	author = "Jackrel, Meredith E and Yee, Keolamau and Tariq, Amber and Chen, Annie I and Shorter, James",
    	doi = "10.1021/acschembio.5b00765",
    	issn = "1554-8937",
    	journal = "ACS chemical biology",
    	month = "dec",
    	number = 12,
    	pages = "2672--9",
    	pmid = 26441009,
    	title = "{Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26441009",
    	volume = 10,
    	year = 2015
    }
    
  4. Meredith E Jackrel and James Shorter.
    Engineering enhanced protein disaggregases for neurodegenerative disease.. Prion 9(2):90–109, January 2015.
    Abstract Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious $\alpha$-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.
    URL, DOI BibTeX

    @article{Jackrel2015,
    	abstract = "Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious $\alpha$-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.",
    	author = "Jackrel, Meredith E and Shorter, James",
    	doi = "10.1080/19336896.2015.1020277",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jackrel, Shorter - 2015 - Engineering enhanced protein disaggregases for neurodegenerative disease.pdf:pdf",
    	issn = "1933-690X",
    	journal = "Prion",
    	keywords = "Amyloid,Amyloid: metabolism,Calmodulin-Binding Proteins,Calmodulin-Binding Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Humans,Models, Molecular,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Protein Engineering,Protein Folding,RNA-Binding Proteins,RNA-Binding Proteins: metabolism,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: metabolism",
    	month = "jan",
    	number = 2,
    	pages = "90--109",
    	pmid = 25738979,
    	title = "{Engineering enhanced protein disaggregases for neurodegenerative disease.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4601286\&tool=pmcentrez\&rendertype=abstract",
    	volume = 9,
    	year = 2015
    }
    
  5. Meredith E Jackrel, Amber Tariq, Keolamau Yee, Rachel Weitzman and James Shorter.
    Isolating potentiated Hsp104 variants using yeast proteinopathy models.. Journal of visualized experiments : JoVE (93):e52089, January 2014.
    Abstract Many protein-misfolding disorders can be modeled in the budding yeast Saccharomyces cerevisiae. Proteins such as TDP-43 and FUS, implicated in amyotrophic lateral sclerosis, and $\alpha$-synuclein, implicated in Parkinson's disease, are toxic and form cytoplasmic aggregates in yeast. These features recapitulate protein pathologies observed in patients with these disorders. Thus, yeast are an ideal platform for isolating toxicity suppressors from libraries of protein variants. We are interested in applying protein disaggregases to eliminate misfolded toxic protein conformers. Specifically, we are engineering Hsp104, a hexameric AAA+ protein from yeast that is uniquely capable of solubilizing both disordered aggregates and amyloid and returning the proteins to their native conformations. While Hsp104 is highly conserved in eukaryotes and eubacteria, it has no known metazoan homologue. Hsp104 has only limited ability to eliminate disordered aggregates and amyloid fibers implicated in human disease. Thus, we aim to engineer Hsp104 variants to reverse the protein misfolding implicated in neurodegenerative disorders. We have developed methods to screen large libraries of Hsp104 variants for suppression of proteotoxicity in yeast. As yeast are prone to spontaneous nonspecific suppression of toxicity, a two-step screening process has been developed to eliminate false positives. Using these methods, we have identified a series of potentiated Hsp104 variants that potently suppress the toxicity and aggregation of TDP-43, FUS, and $\alpha$-synuclein. Here, we describe this optimized protocol, which could be adapted to screen libraries constructed using any protein backbone for suppression of toxicity of any protein that is toxic in yeast.
    URL, DOI BibTeX

    @article{Jackrel2014b,
    	abstract = "Many protein-misfolding disorders can be modeled in the budding yeast Saccharomyces cerevisiae. Proteins such as TDP-43 and FUS, implicated in amyotrophic lateral sclerosis, and $\alpha$-synuclein, implicated in Parkinson's disease, are toxic and form cytoplasmic aggregates in yeast. These features recapitulate protein pathologies observed in patients with these disorders. Thus, yeast are an ideal platform for isolating toxicity suppressors from libraries of protein variants. We are interested in applying protein disaggregases to eliminate misfolded toxic protein conformers. Specifically, we are engineering Hsp104, a hexameric AAA+ protein from yeast that is uniquely capable of solubilizing both disordered aggregates and amyloid and returning the proteins to their native conformations. While Hsp104 is highly conserved in eukaryotes and eubacteria, it has no known metazoan homologue. Hsp104 has only limited ability to eliminate disordered aggregates and amyloid fibers implicated in human disease. Thus, we aim to engineer Hsp104 variants to reverse the protein misfolding implicated in neurodegenerative disorders. We have developed methods to screen large libraries of Hsp104 variants for suppression of proteotoxicity in yeast. As yeast are prone to spontaneous nonspecific suppression of toxicity, a two-step screening process has been developed to eliminate false positives. Using these methods, we have identified a series of potentiated Hsp104 variants that potently suppress the toxicity and aggregation of TDP-43, FUS, and $\alpha$-synuclein. Here, we describe this optimized protocol, which could be adapted to screen libraries constructed using any protein backbone for suppression of toxicity of any protein that is toxic in yeast.",
    	author = "Jackrel, Meredith E and Tariq, Amber and Yee, Keolamau and Weitzman, Rachel and Shorter, James",
    	doi = "10.3791/52089",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jackrel et al. - 2014 - Isolating potentiated Hsp104 variants using yeast proteinopathy models.pdf:pdf",
    	issn = "1940-087X",
    	journal = "Journal of visualized experiments : JoVE",
    	keywords = "DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Heat-Shock Proteins: toxicity,Parkinson Disease,Parkinson Disease: metabolism,Peptide Library,Protein Conformation,RNA-Binding Protein FUS,RNA-Binding Protein FUS: metabolism,Saccharomyces cerevisiae,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: metabolism,Saccharomyces cerevisiae: metabolism,alpha-Synuclein,alpha-Synuclein: metabolism",
    	month = "jan",
    	number = 93,
    	pages = "e52089",
    	pmid = 25407485,
    	title = "{Isolating potentiated Hsp104 variants using yeast proteinopathy models.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4238040\&tool=pmcentrez\&rendertype=abstract",
    	year = 2014
    }
    
  6. Meredith E Jackrel and James Shorter.
    Reversing deleterious protein aggregation with re-engineered protein disaggregases.. Cell cycle (Georgetown, Tex.) 13(9):1379–83, January 2014.
    Abstract Aberrant protein folding is severely problematic and manifests in numerous disorders, including amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington disease (HD), and Alzheimer disease (AD). Patients with each of these disorders are characterized by the accumulation of mislocalized protein deposits. Treatments for these disorders remain palliative, and no available therapeutics eliminate the underlying toxic conformers. An intriguing approach to reverse deleterious protein misfolding is to upregulate chaperones to restore proteostasis. We recently reported our work to re-engineer a prion disaggregase from yeast, Hsp104, to reverse protein misfolding implicated in human disease. These potentiated Hsp104 variants suppress TDP-43, FUS, and $\alpha$-synuclein toxicity in yeast, eliminate aggregates, reverse cellular mislocalization, and suppress dopaminergic neurodegeneration in an animal model of PD. Here, we discuss this work and its context, as well as approaches for further developing potentiated Hsp104 variants for application in reversing protein-misfolding disorders.
    URL, DOI BibTeX

    @article{Jackrel2014a,
    	abstract = "Aberrant protein folding is severely problematic and manifests in numerous disorders, including amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington disease (HD), and Alzheimer disease (AD). Patients with each of these disorders are characterized by the accumulation of mislocalized protein deposits. Treatments for these disorders remain palliative, and no available therapeutics eliminate the underlying toxic conformers. An intriguing approach to reverse deleterious protein misfolding is to upregulate chaperones to restore proteostasis. We recently reported our work to re-engineer a prion disaggregase from yeast, Hsp104, to reverse protein misfolding implicated in human disease. These potentiated Hsp104 variants suppress TDP-43, FUS, and $\alpha$-synuclein toxicity in yeast, eliminate aggregates, reverse cellular mislocalization, and suppress dopaminergic neurodegeneration in an animal model of PD. Here, we discuss this work and its context, as well as approaches for further developing potentiated Hsp104 variants for application in reversing protein-misfolding disorders.",
    	author = "Jackrel, Meredith E and Shorter, James",
    	doi = "10.4161/cc.28709",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jackrel, Shorter - 2014 - Reversing deleterious protein aggregation with re-engineered protein disaggregases.pdf:pdf",
    	issn = "1551-4005",
    	journal = "Cell cycle (Georgetown, Tex.)",
    	keywords = "Animals,Animals, Genetically Modified,Caenorhabditis elegans,Caenorhabditis elegans: genetics,Caenorhabditis elegans: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Molecular Chaperones,Molecular Chaperones: genetics,Molecular Chaperones: metabolism,Protein Aggregation, Pathological,Protein Aggregation, Pathological: genetics,Protein Aggregation, Pathological: metabolism,Protein Aggregation, Pathological: prevention \& co,Protein Engineering,Proteostasis Deficiencies,Proteostasis Deficiencies: genetics,Proteostasis Deficiencies: metabolism,Proteostasis Deficiencies: prevention \& control,Saccharomyces cerevisiae,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: genetics,Saccharomyces cerevisiae Proteins: metabolism,Saccharomyces cerevisiae: genetics,Saccharomyces cerevisiae: metabolism",
    	month = "jan",
    	number = 9,
    	pages = "1379--83",
    	pmid = 24694655,
    	title = "{Reversing deleterious protein aggregation with re-engineered protein disaggregases.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4050135\&tool=pmcentrez\&rendertype=abstract",
    	volume = 13,
    	year = 2014
    }
    
  7. Meredith E Jackrel, Morgan E DeSantis, Bryan A Martinez, Laura M Castellano, Rachel M Stewart, Kim A Caldwell, Guy A Caldwell and James Shorter.
    Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events.. Cell 156(1-2):170–82, January 2014.
    Abstract There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and $\alpha$-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.
    URL, DOI BibTeX

    @article{Jackrel2014,
    	abstract = "There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and $\alpha$-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.",
    	author = "Jackrel, Meredith E and DeSantis, Morgan E and Martinez, Bryan A and Castellano, Laura M and Stewart, Rachel M and Caldwell, Kim A and Caldwell, Guy A and Shorter, James",
    	doi = "10.1016/j.cell.2013.11.047",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jackrel et al. - 2014 - Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events.pdf:pdf",
    	issn = "1097-4172",
    	journal = "Cell",
    	keywords = "Animals,Animals, Genetically Modified,Caenorhabditis elegans,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Disease Models, Animal,Heat-Shock Proteins,Heat-Shock Proteins: chemistry,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Models, Molecular,Mutagenesis,Neurons,Neurons: cytology,Neurons: pathology,Parkinson Disease,Parkinson Disease: metabolism,Parkinson Disease: pathology,Parkinson Disease: therapy,Protein Folding,Protein Structure, Tertiary,Proteostasis Deficiencies,Proteostasis Deficiencies: metabolism,Proteostasis Deficiencies: pathology,Proteostasis Deficiencies: therapy,RNA-Binding Protein FUS,RNA-Binding Protein FUS: metabolism,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: chemistry,Saccharomyces cerevisiae Proteins: genetics,Saccharomyces cerevisiae Proteins: metabolism,alpha-Synuclein,alpha-Synuclein: metabolism",
    	month = "jan",
    	number = "1-2",
    	pages = "170--82",
    	pmid = 24439375,
    	title = "{Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3909490\&tool=pmcentrez\&rendertype=abstract",
    	volume = 156,
    	year = 2014
    }
    
  8. Parveen Salahuddin, Gulam Rabbani and Rizwan Hasan Khan.
    The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach.. Cellular & molecular biology letters 19(3):407–37, 2014.
    Abstract Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies have shown that glycation induces the formation of the $\beta$-sheet structure in $\beta$-amyloid protein, $\alpha$-synuclein, transthyretin (TTR), copper-zinc superoxide dismutase 1 (Cu, Zn-SOD-1), and prion protein. Aggregation of the $\beta$-sheet structure in each case creates fibrillar structures, respectively causing Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and prion disease. It has been suggested that oligomeric species of glycated $\alpha$-synuclein and prion are more toxic than fibrils. This review focuses on the pathway of AGE formation, the synthesis of different types of AGE, and the molecular mechanisms by which glycation causes various types of neurodegenerative disease. It discusses several new therapeutic approaches that have been applied to treat these devastating disorders, including the use of various synthetic and naturally occurring inhibitors. Modulation of the AGE-RAGE axis is now considered promising in the prevention of neurodegenerative diseases. Additionally, the review covers several defense enzymes and proteins in the human body that are important anti-glycating systems acting to prevent the development of neurodegenerative diseases.
    URL, DOI BibTeX

    @article{Salahuddin2014,
    	abstract = "Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies have shown that glycation induces the formation of the $\beta$-sheet structure in $\beta$-amyloid protein, $\alpha$-synuclein, transthyretin (TTR), copper-zinc superoxide dismutase 1 (Cu, Zn-SOD-1), and prion protein. Aggregation of the $\beta$-sheet structure in each case creates fibrillar structures, respectively causing Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and prion disease. It has been suggested that oligomeric species of glycated $\alpha$-synuclein and prion are more toxic than fibrils. This review focuses on the pathway of AGE formation, the synthesis of different types of AGE, and the molecular mechanisms by which glycation causes various types of neurodegenerative disease. It discusses several new therapeutic approaches that have been applied to treat these devastating disorders, including the use of various synthetic and naturally occurring inhibitors. Modulation of the AGE-RAGE axis is now considered promising in the prevention of neurodegenerative diseases. Additionally, the review covers several defense enzymes and proteins in the human body that are important anti-glycating systems acting to prevent the development of neurodegenerative diseases.",
    	author = "Salahuddin, Parveen and Rabbani, Gulam and Khan, Rizwan Hasan",
    	doi = "10.2478/s11658-014-0205-5",
    	issn = "1689-1392",
    	journal = "Cellular \& molecular biology letters",
    	month = "",
    	number = 3,
    	pages = "407--37",
    	pmid = 25141979,
    	title = "{The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25141979",
    	volume = 19,
    	year = 2014
    }
    
  9. Helen R Broom, Jessica A O Rumfeldt and Elizabeth M Meiering.
    Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis.. Essays in biochemistry 56:149–65, January 2014.
    Abstract ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell-cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.
    URL, DOI BibTeX

    @article{Broom2014,
    	abstract = "ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell-cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.",
    	author = "Broom, Helen R and Rumfeldt, Jessica A O and Meiering, Elizabeth M",
    	doi = "10.1042/bse0560149",
    	issn = "1744-1358",
    	journal = "Essays in biochemistry",
    	month = "jan",
    	pages = "149--65",
    	pmid = 25131593,
    	title = "{Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25131593",
    	volume = 56,
    	year = 2014
    }
    
  10. Ali Chaari, Jessica Hoarau-Véchot and Moncef Ladjimi.
    Applying chaperones to protein-misfolding disorders: molecular chaperones against $\alpha$-synuclein in Parkinson's disease.. International journal of biological macromolecules 60:196–205, September 2013.
    Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called $\alpha$-synuclein ($\alpha$-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows $\alpha$-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing $\alpha$-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD.
    URL, DOI BibTeX

    @article{Chaari2013,
    	abstract = "Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called $\alpha$-synuclein ($\alpha$-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows $\alpha$-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing $\alpha$-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD.",
    	author = "Chaari, Ali and Hoarau-V\'{e}chot, Jessica and Ladjimi, Moncef",
    	doi = "10.1016/j.ijbiomac.2013.05.032",
    	issn = "1879-0003",
    	journal = "International journal of biological macromolecules",
    	keywords = "Animals,Biomarkers,Heat-Shock Proteins,Heat-Shock Proteins: chemistry,Heat-Shock Proteins: metabolism,Humans,Lewy Bodies,Lewy Bodies: metabolism,Molecular Chaperones,Molecular Chaperones: chemistry,Molecular Chaperones: metabolism,Parkinson Disease,Parkinson Disease: metabolism,Parkinson Disease: pathology,Protein Folding,Proteostasis Deficiencies,Proteostasis Deficiencies: metabolism,alpha-Synuclein,alpha-Synuclein: chemistry,alpha-Synuclein: metabolism",
    	month = "sep",
    	pages = "196--205",
    	pmid = 23748003,
    	title = "{Applying chaperones to protein-misfolding disorders: molecular chaperones against $\alpha$-synuclein in Parkinson's disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23748003",
    	volume = 60,
    	year = 2013
    }
    
  11. Qian Ma, Ji-Ying Hu, Jie Chen and Yi Liang.
    The role of crowded physiological environments in prion and prion-like protein aggregation.. International journal of molecular sciences 14(11):21339–52, January 2013.
    Abstract Prion diseases and prion-like protein misfolding diseases are related to the accumulation of abnormal aggregates of the normal host proteins including prion proteins and Tau protein. These proteins possess self-templating and transmissible characteristics. The crowded physiological environments where the aggregation of these amyloidogenic proteins takes place can be imitated in vitro by the addition of macromolecular crowding agents such as inert polysaccharides. In this review, we summarize the aggregation of prion proteins in crowded physiological environments and discuss the role of macromolecular crowding in prion protein aggregation. We also summarize the aggregation of prion-like proteins including human Tau protein, human $\alpha$-synuclein, and human copper, zinc superoxide dismutase under macromolecular crowding environments and discuss the role of macromolecular crowding in prion-like protein aggregation. The excluded-volume effects caused by macromolecular crowding could accelerate the aggregation of neurodegenerative disease-associated proteins while inhibiting the aggregation of the proteins that are not neurodegenerative disease-associated.
    URL, DOI BibTeX

    @article{Ma2013,
    	abstract = "Prion diseases and prion-like protein misfolding diseases are related to the accumulation of abnormal aggregates of the normal host proteins including prion proteins and Tau protein. These proteins possess self-templating and transmissible characteristics. The crowded physiological environments where the aggregation of these amyloidogenic proteins takes place can be imitated in vitro by the addition of macromolecular crowding agents such as inert polysaccharides. In this review, we summarize the aggregation of prion proteins in crowded physiological environments and discuss the role of macromolecular crowding in prion protein aggregation. We also summarize the aggregation of prion-like proteins including human Tau protein, human $\alpha$-synuclein, and human copper, zinc superoxide dismutase under macromolecular crowding environments and discuss the role of macromolecular crowding in prion-like protein aggregation. The excluded-volume effects caused by macromolecular crowding could accelerate the aggregation of neurodegenerative disease-associated proteins while inhibiting the aggregation of the proteins that are not neurodegenerative disease-associated.",
    	author = "Ma, Qian and Hu, Ji-Ying and Chen, Jie and Liang, Yi",
    	doi = "10.3390/ijms141121339",
    	issn = "1422-0067",
    	journal = "International journal of molecular sciences",
    	keywords = "Humans,Neurodegenerative Diseases,Neurodegenerative Diseases: etiology,Neurodegenerative Diseases: metabolism,Neurodegenerative Diseases: pathology,Prions,Prions: chemistry,Prions: genetics,Prions: metabolism,alpha-Synuclein,alpha-Synuclein: chemistry,alpha-Synuclein: genetics,alpha-Synuclein: metabolism,tau Proteins,tau Proteins: chemistry,tau Proteins: metabolism",
    	month = "jan",
    	number = 11,
    	pages = "21339--52",
    	pmid = 24284393,
    	title = "{The role of crowded physiological environments in prion and prion-like protein aggregation.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3856008\&tool=pmcentrez\&rendertype=abstract",
    	volume = 14,
    	year = 2013
    }
    
  12. Sergio Camero, Mar\'ıa J Ben\'ıtez and Juan S Jiménez.
    Anomalous protein-DNA interactions behind neurological disorders.. Advances in protein chemistry and structural biology 91:37–63, January 2013.
    Abstract Aggregation, nuclear location, and nucleic acid interaction are common features shared by a number of proteins related to neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, transmissible spongiform encephalopathy, Huntington's disease, spinobulbar muscular atrophy, dentatorubro-pallidoluysian atrophy, and several spinocerebellar ataxias. $\beta$-Amyloid peptides, tau protein, $\alpha$-synuclein, superoxide dismutase1, prion protein, huntingtin, atrophin1, androgen receptor, and several ataxins are proteins prone to becoming aggregated, to translocate inside cell nucleus, and to bind DNA. In this chapter, we review those common features suggesting that neurological diseases too may share a transcriptional disorder, making it an important contribution to the origin of the disease.
    URL, DOI BibTeX

    @article{Camero2013,
    	abstract = "Aggregation, nuclear location, and nucleic acid interaction are common features shared by a number of proteins related to neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, transmissible spongiform encephalopathy, Huntington's disease, spinobulbar muscular atrophy, dentatorubro-pallidoluysian atrophy, and several spinocerebellar ataxias. $\beta$-Amyloid peptides, tau protein, $\alpha$-synuclein, superoxide dismutase1, prion protein, huntingtin, atrophin1, androgen receptor, and several ataxins are proteins prone to becoming aggregated, to translocate inside cell nucleus, and to bind DNA. In this chapter, we review those common features suggesting that neurological diseases too may share a transcriptional disorder, making it an important contribution to the origin of the disease.",
    	author = "Camero, Sergio and Ben\'{\i}tez, Mar\'{\i}a J and Jim\'{e}nez, Juan S",
    	doi = "10.1016/B978-0-12-411637-5.00002-0",
    	issn = "1876-1631",
    	journal = "Advances in protein chemistry and structural biology",
    	keywords = "DNA,DNA: chemistry,DNA: metabolism,Humans,Nervous System Diseases,Nervous System Diseases: metabolism,Nervous System Diseases: pathology,Proteins,Proteins: chemistry,Proteins: metabolism",
    	month = "jan",
    	pages = "37--63",
    	pmid = 23790210,
    	title = "{Anomalous protein-DNA interactions behind neurological disorders.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23790210",
    	volume = 91,
    	year = 2013
    }
    
  13. Dmitry Kryndushkin, Gudrun Ihrke, Tetsade C Piermartiri and Frank Shewmaker.
    A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity.. Molecular microbiology 86(6):1531–47, December 2012.
    Abstract Many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) are linked to the accumulation of specific protein aggregates in affected regions of the nervous system. SOD1, TDP-43, FUS and optineurin (OPTN) proteins were identified to form intraneuronal inclusions in ALS patients. In addition, mutations in OPTN are associated with both ALS and glaucoma. As the pathological role of OPTN in neuronal degeneration remains unresolved, we created a yeast model to study its potential for aggregation and toxicity. We observed that both wild type and disease-associated mutants of OPTN form toxic non-amyloid aggregates in yeast. Similar to reported cell culture and mouse models, the OPTN E50K mutant shows enhanced toxicity in yeast, implying a conserved gain-of-function mechanism. Furthermore, OPTN shows a unique aggregation pattern compared to other disease-related proteins in yeast. OPTN aggregates colocalize only partially with the insoluble protein deposit (IPOD) site markers, but coincide perfectly with the prion seed-reducing protein Btn2 and several other aggregation-prone proteins, suggesting that protein aggregates are not limited to a single IPOD site. Importantly, changes in the Btn2p level modify OPTN toxicity and aggregation. This study generates a mechanistic framework for investigating how OPTN may trigger pathological changes in ALS and other OPTN-linked neurodegenerative disorders.
    URL, DOI BibTeX

    @article{Kryndushkin2012,
    	abstract = "Many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) are linked to the accumulation of specific protein aggregates in affected regions of the nervous system. SOD1, TDP-43, FUS and optineurin (OPTN) proteins were identified to form intraneuronal inclusions in ALS patients. In addition, mutations in OPTN are associated with both ALS and glaucoma. As the pathological role of OPTN in neuronal degeneration remains unresolved, we created a yeast model to study its potential for aggregation and toxicity. We observed that both wild type and disease-associated mutants of OPTN form toxic non-amyloid aggregates in yeast. Similar to reported cell culture and mouse models, the OPTN E50K mutant shows enhanced toxicity in yeast, implying a conserved gain-of-function mechanism. Furthermore, OPTN shows a unique aggregation pattern compared to other disease-related proteins in yeast. OPTN aggregates colocalize only partially with the insoluble protein deposit (IPOD) site markers, but coincide perfectly with the prion seed-reducing protein Btn2 and several other aggregation-prone proteins, suggesting that protein aggregates are not limited to a single IPOD site. Importantly, changes in the Btn2p level modify OPTN toxicity and aggregation. This study generates a mechanistic framework for investigating how OPTN may trigger pathological changes in ALS and other OPTN-linked neurodegenerative disorders.",
    	author = "Kryndushkin, Dmitry and Ihrke, Gudrun and Piermartiri, Tetsade C and Shewmaker, Frank",
    	doi = "10.1111/mmi.12075",
    	issn = "1365-2958",
    	journal = "Molecular microbiology",
    	keywords = "Amino Acid Transport Systems,Amino Acid Transport Systems: metabolism,Cell Line,Humans,Mutant Proteins,Mutant Proteins: metabolism,Mutant Proteins: toxicity,Mutation, Missense,Protein Denaturation,Protein Multimerization,Saccharomyces cerevisiae,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: metabolism,Saccharomyces cerevisiae: metabolism,Transcription Factor TFIIIA,Transcription Factor TFIIIA: metabolism,Transcription Factor TFIIIA: toxicity",
    	month = "dec",
    	number = 6,
    	pages = "1531--47",
    	pmid = 23078282,
    	title = "{A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23078282",
    	volume = 86,
    	year = 2012
    }
    
  14. Lori Krim Gavrin, Rajiah Aldrin Denny and Eddine Saiah.
    Small molecules that target protein misfolding.. Journal of medicinal chemistry 55(24):10823–43, 2012.
    Abstract Protein misfolding is a process in which proteins are unable to attain or maintain their biologically active conformation. Factors contributing to protein misfolding include missense mutations and intracellular factors such as pH changes, oxidative stress, or metal ions. Protein misfolding is linked to a large number of diseases such as cystic fibrosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and less familiar diseases such as Gaucher's disease, nephrogenic diabetes insipidus, and Creutzfeldt-Jakob disease. In this Perspective, we report on small molecules that bind to and stabilize the aberrant protein, thereby helping it to attain a native or near-native conformation and restoring its function. The following targets will be specifically discussed: transthyretin, p53, superoxide dismutase 1, lysozyme, serum amyloid A, prions, vasopressin receptor 2, and $\alpha$-1-antitrypsin.
    URL, DOI BibTeX

    @article{Gavrin2012,
    	abstract = "Protein misfolding is a process in which proteins are unable to attain or maintain their biologically active conformation. Factors contributing to protein misfolding include missense mutations and intracellular factors such as pH changes, oxidative stress, or metal ions. Protein misfolding is linked to a large number of diseases such as cystic fibrosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and less familiar diseases such as Gaucher's disease, nephrogenic diabetes insipidus, and Creutzfeldt-Jakob disease. In this Perspective, we report on small molecules that bind to and stabilize the aberrant protein, thereby helping it to attain a native or near-native conformation and restoring its function. The following targets will be specifically discussed: transthyretin, p53, superoxide dismutase 1, lysozyme, serum amyloid A, prions, vasopressin receptor 2, and $\alpha$-1-antitrypsin.",
    	author = "Gavrin, Lori Krim and Denny, Rajiah Aldrin and Saiah, Eddine",
    	doi = "10.1021/jm301182j",
    	issn = "1520-4804",
    	journal = "Journal of medicinal chemistry",
    	keywords = "Amyloid,Amyloid: metabolism,Animals,Humans,Models, Molecular,Muramidase,Muramidase: chemistry,Muramidase: physiology,Mutation,Neurodegenerative Diseases,Neurodegenerative Diseases: drug therapy,Neurodegenerative Diseases: metabolism,Prealbumin,Prealbumin: chemistry,Prealbumin: physiology,Prions,Prions: chemistry,Prions: physiology,Protein Binding,Protein Conformation,Protein Folding,Proteins,Proteins: chemistry,Proteins: physiology,Proteostasis Deficiencies,Proteostasis Deficiencies: drug therapy,Proteostasis Deficiencies: metabolism,Receptors, Vasopressin,Receptors, Vasopressin: chemistry,Receptors, Vasopressin: physiology,Serum Amyloid A Protein,Serum Amyloid A Protein: chemistry,Serum Amyloid A Protein: physiology,Small Molecule Libraries,Small Molecule Libraries: chemistry,Small Molecule Libraries: pharmacology,Superoxide Dismutase,Superoxide Dismutase: chemistry,Superoxide Dismutase: physiology,Tumor Suppressor Protein p53,Tumor Suppressor Protein p53: chemistry,Tumor Suppressor Protein p53: physiology,Unfolded Protein Response,alpha 1-Antitrypsin,alpha 1-Antitrypsin: chemistry,alpha 1-Antitrypsin: physiology",
    	month = "",
    	number = 24,
    	pages = "10823--43",
    	pmid = 23075044,
    	title = "{Small molecules that target protein misfolding.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23075044",
    	volume = 55,
    	year = 2012
    }
    
  15. Yoshiaki Furukawa.
    Pathological roles of wild-type cu, zn-superoxide dismutase in amyotrophic lateral sclerosis.. Neurology research international 2012:323261, January 2012.
    Abstract Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, many in vitro and in vivo studies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations in sod1 gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.
    URL, DOI BibTeX

    @article{Furukawa2012,
    	abstract = "Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, many in vitro and in vivo studies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations in sod1 gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.",
    	author = "Furukawa, Yoshiaki",
    	doi = "10.1155/2012/323261",
    	issn = "2090-1860",
    	journal = "Neurology research international",
    	month = "jan",
    	pages = 323261,
    	pmid = 22830015,
    	title = "{Pathological roles of wild-type cu, zn-superoxide dismutase in amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3395178\&tool=pmcentrez\&rendertype=abstract",
    	volume = 2012,
    	year = 2012
    }
    
  16. Shayne A Bellingham, Belinda B Guo, Bradley M Coleman and Andrew F Hill.
    Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?. Frontiers in physiology 3:124, 2012.
    Abstract Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including A$\beta$. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.
    URL, DOI BibTeX

    @article{Bellingham2012,
    	abstract = "Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including A$\beta$. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.",
    	author = "Bellingham, Shayne A and Guo, Belinda B and Coleman, Bradley M and Hill, Andrew F",
    	doi = "10.3389/fphys.2012.00124",
    	issn = "1664-042X",
    	journal = "Frontiers in physiology",
    	month = "",
    	pages = 124,
    	pmid = 22563321,
    	title = "{Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3342525\&tool=pmcentrez\&rendertype=abstract",
    	volume = 3,
    	year = 2012
    }
    
  17. Magdalini Polymenidou and Don W Cleveland.
    The seeds of neurodegeneration: prion-like spreading in ALS.. Cell 147(3):498–508, October 2011.
    Abstract Misfolded proteins accumulating in several neurodegenerative diseases (including Alzheimer, Parkinson, and Huntington diseases) can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its cellular isoform. Evidence for such a prion-like mechanism has now spread to the main misfolded proteins, SOD1 and TDP-43, implicated in amyotrophic lateral sclerosis (ALS). The major neurodegenerative diseases may therefore have mechanistic parallels for non-cell-autonomous spread of disease within the nervous system.
    URL, DOI BibTeX

    @article{Polymenidou2011,
    	abstract = "Misfolded proteins accumulating in several neurodegenerative diseases (including Alzheimer, Parkinson, and Huntington diseases) can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its cellular isoform. Evidence for such a prion-like mechanism has now spread to the main misfolded proteins, SOD1 and TDP-43, implicated in amyotrophic lateral sclerosis (ALS). The major neurodegenerative diseases may therefore have mechanistic parallels for non-cell-autonomous spread of disease within the nervous system.",
    	author = "Polymenidou, Magdalini and Cleveland, Don W",
    	doi = "10.1016/j.cell.2011.10.011",
    	issn = "1097-4172",
    	journal = "Cell",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Animals,Humans,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Prions,Prions: metabolism,Protein Folding",
    	month = "oct",
    	number = 3,
    	pages = "498--508",
    	pmid = 22036560,
    	title = "{The seeds of neurodegeneration: prion-like spreading in ALS.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3220614\&tool=pmcentrez\&rendertype=abstract",
    	volume = 147,
    	year = 2011
    }
    
  18. Petra Steinacker, Andreas Hawlik, Stefan Lehnert, Olaf Jahn, Stephen Meier, Evamaria Görz, Kerstin E Braunstein, Marija Krzovska, Birgit Schwalenstöcker, Sarah Jesse, Christian Pröpper, Tobias Böckers, Albert Ludolph and Markus Otto.
    Neuroprotective function of cellular prion protein in a mouse model of amyotrophic lateral sclerosis.. The American journal of pathology 176(3):1409–20, 2010.
    Abstract Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1G93A mouse in a cross-breeding strategy to study the function of physiological prion protein (Prp). SOD1G93APrp-/- mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1G93APrp+/+ mice. Additionally, during disease progression, SOD1G93APrp-/- mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1G93APrp-/- mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1G93APrp-/- versus SOD1G93A mice. In the course of disease, Bcl-2 decreases, nuclear factor-kappaB increases, and Akt is activated, but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice, we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense, rather than anti-apoptotic signaling.
    URL, DOI BibTeX

    @article{Steinacker2010,
    	abstract = "Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1G93A mouse in a cross-breeding strategy to study the function of physiological prion protein (Prp). SOD1G93APrp-/- mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1G93APrp+/+ mice. Additionally, during disease progression, SOD1G93APrp-/- mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1G93APrp-/- mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1G93APrp-/- versus SOD1G93A mice. In the course of disease, Bcl-2 decreases, nuclear factor-kappaB increases, and Akt is activated, but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice, we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense, rather than anti-apoptotic signaling.",
    	author = {Steinacker, Petra and Hawlik, Andreas and Lehnert, Stefan and Jahn, Olaf and Meier, Stephen and G\"{o}rz, Evamaria and Braunstein, Kerstin E and Krzovska, Marija and Schwalenst\"{o}cker, Birgit and Jesse, Sarah and Pr\"{o}pper, Christian and B\"{o}ckers, Tobias and Ludolph, Albert and Otto, Markus},
    	doi = "10.2353/ajpath.2010.090355",
    	issn = "1525-2191",
    	journal = "The American journal of pathology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Brain,Brain: enzymology,Brain: pathology,Breeding,Cell Count,DNA,DNA: metabolism,Disease Models, Animal,Disease Progression,Enzyme Activation,Female,Glial Fibrillary Acidic Protein,Glial Fibrillary Acidic Protein: metabolism,Humans,Male,Mice,Mice, Transgenic,Mitogen-Activated Protein Kinase 1,Mitogen-Activated Protein Kinase 1: metabolism,Motor Neurons,Motor Neurons: pathology,Neuroprotective Agents,Neuroprotective Agents: metabolism,Prions,Prions: metabolism,Spinal Cord,Spinal Cord: enzymology,Spinal Cord: pathology,Superoxide Dismutase,Superoxide Dismutase: genetics,Survival Analysis,Transgenes,Transgenes: genetics,Vacuoles,Vacuoles: metabolism",
    	month = "",
    	number = 3,
    	pages = "1409--20",
    	pmid = 20075202,
    	title = "{Neuroprotective function of cellular prion protein in a mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2832160\&tool=pmcentrez\&rendertype=abstract",
    	volume = 176,
    	year = 2010
    }
    
  19. Juan S Jiménez.
    Protein-DNA interaction at the origin of neurological diseases: a hypothesis.. Journal of Alzheimer's disease : JAD 22(2):375–91, January 2010.
    Abstract A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-$\beta$, tau protein, $\alpha$-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, $\alpha$ 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation.
    URL, DOI BibTeX

    @article{Jimenez2010,
    	abstract = "A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-$\beta$, tau protein, $\alpha$-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, $\alpha$ 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation.",
    	author = "Jim\'{e}nez, Juan S",
    	doi = "10.3233/JAD-2010-100189",
    	issn = "1875-8908",
    	journal = "Journal of Alzheimer's disease : JAD",
    	keywords = "Animals,DNA,DNA: metabolism,Humans,Nervous System Diseases,Nervous System Diseases: etiology,Nervous System Diseases: genetics,Nervous System Diseases: metabolism,Proteins,Proteins: metabolism",
    	month = "jan",
    	number = 2,
    	pages = "375--91",
    	pmid = 20847445,
    	title = "{Protein-DNA interaction at the origin of neurological diseases: a hypothesis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/20847445",
    	volume = 22,
    	year = 2010
    }
    
  20. Ruth Chia, Howard M Tattum, Samantha Jones, John Collinge, Elizabeth M C Fisher and Graham S Jackson.
    Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.. PloS one 5(5):e10627, January 2010.
    Abstract BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal centre of weakness, such as one limb, and appears to spread to other parts of the body. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s). Although different mutations lead to varying tendencies of SOD1 to aggregate, we suggest abnormal proteins share a common misfolding pathway that leads to the formation of amyloid fibrils. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that misfolding of superoxide dismutase 1 leads to the formation of amyloid fibrils associated with seeding activity, which can accelerate the formation of new fibrils in an autocatalytic cascade. The time limiting event is nucleation to form a stable protein "seed" before a rapid linear polymerisation results in amyloid fibrils analogous to other protein misfolding disorders. This phenomenon was not confined to fibrils of recombinant protein as here we show, for the first time, that spinal cord homogenates obtained from a transgenic mouse model that overexpresses mutant human superoxide dismutase 1 (the TgSOD1(G93A) mouse) also contain amyloid seeds that accelerate the formation of new fibrils in both wildtype and mutant SOD1 protein in vitro. CONCLUSIONS/SIGNIFICANCE: These findings provide new insights into ALS disease mechanism and in particular a mechanism that could account for the spread of pathology throughout the nervous system. This model of disease spread, which has analogies to other protein misfolding disorders such as prion disease, also suggests it may be possible to design assays for therapeutics that can inhibit fibril propagation and hence, possibly, disease progression.
    URL, DOI BibTeX

    @article{Chia2010,
    	abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal centre of weakness, such as one limb, and appears to spread to other parts of the body. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s). Although different mutations lead to varying tendencies of SOD1 to aggregate, we suggest abnormal proteins share a common misfolding pathway that leads to the formation of amyloid fibrils. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that misfolding of superoxide dismutase 1 leads to the formation of amyloid fibrils associated with seeding activity, which can accelerate the formation of new fibrils in an autocatalytic cascade. The time limiting event is nucleation to form a stable protein "seed" before a rapid linear polymerisation results in amyloid fibrils analogous to other protein misfolding disorders. This phenomenon was not confined to fibrils of recombinant protein as here we show, for the first time, that spinal cord homogenates obtained from a transgenic mouse model that overexpresses mutant human superoxide dismutase 1 (the TgSOD1(G93A) mouse) also contain amyloid seeds that accelerate the formation of new fibrils in both wildtype and mutant SOD1 protein in vitro. CONCLUSIONS/SIGNIFICANCE: These findings provide new insights into ALS disease mechanism and in particular a mechanism that could account for the spread of pathology throughout the nervous system. This model of disease spread, which has analogies to other protein misfolding disorders such as prion disease, also suggests it may be possible to design assays for therapeutics that can inhibit fibril propagation and hence, possibly, disease progression.},
    	author = "Chia, Ruth and Tattum, M Howard and Jones, Samantha and Collinge, John and Fisher, Elizabeth M C and Jackson, Graham S",
    	doi = "10.1371/journal.pone.0010627",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyloid,Amyloid: metabolism,Amyloid: ultrastructure,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: pathology,Animals,Cell Death,Humans,Kinetics,Mice,Mice, Transgenic,Microscopy, Electron,Protein Stability,Spinal Cord,Spinal Cord: enzymology,Spinal Cord: pathology,Spinal Cord: ultrastructure,Subcellular Fractions,Subcellular Fractions: enzymology,Superoxide Dismutase,Superoxide Dismutase: metabolism,Superoxide Dismutase: ultrastructure,Thiazoles,Thiazoles: metabolism,Time Factors",
    	month = "jan",
    	number = 5,
    	pages = "e10627",
    	pmid = 20498711,
    	title = "{Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2869360\&tool=pmcentrez\&rendertype=abstract",
    	volume = 5,
    	year = 2010
    }
    
  21. P G Ince, J Tomkins, J Y Slade, N M Thatcher and P J Shaw.
    Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS.. Journal of neuropathology and experimental neurology 57(10):895–904, 1998.
    Abstract Molecular pathology has identified 2 distinct forms of neuronal inclusion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions are skeins or small dense filamentous aggregates which can only be demonstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline conglomerates (HC) are large multifocal accumulations of neurofilaments. Previous reports have failed to clarify the distinction and relationship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and determine the relevance of molecular events in familial cases to the pathogenesis of sporadic disease. We describe the molecular pathology of 5 ALS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were excluded. Hyaline conglomerate inclusions were detected only in the 2 cases with the SOD1 I113T mutation and showed a widespread multisystem distribution. In contrast ALS-type inclusions characterized sporadic cases (70/73) and were restricted to lower motor neurons. Hyaline conglomerates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that HC contain equally abundant phosphorylated and nonphosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immunoreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal column myelin loss. In 4 cases the motor cortex was normal or only minimally affected. This further illustrates the extent to which upper motor neuron damage in ALS is usually a distal axonopathy. Previously reported pathological accounts of SOD1-related familial ALS (FALS) are reviewed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings suggest the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades.
    URL BibTeX

    @article{Ince1998,
    	abstract = "Molecular pathology has identified 2 distinct forms of neuronal inclusion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions are skeins or small dense filamentous aggregates which can only be demonstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline conglomerates (HC) are large multifocal accumulations of neurofilaments. Previous reports have failed to clarify the distinction and relationship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and determine the relevance of molecular events in familial cases to the pathogenesis of sporadic disease. We describe the molecular pathology of 5 ALS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were excluded. Hyaline conglomerate inclusions were detected only in the 2 cases with the SOD1 I113T mutation and showed a widespread multisystem distribution. In contrast ALS-type inclusions characterized sporadic cases (70/73) and were restricted to lower motor neurons. Hyaline conglomerates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that HC contain equally abundant phosphorylated and nonphosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immunoreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal column myelin loss. In 4 cases the motor cortex was normal or only minimally affected. This further illustrates the extent to which upper motor neuron damage in ALS is usually a distal axonopathy. Previously reported pathological accounts of SOD1-related familial ALS (FALS) are reviewed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings suggest the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades.",
    	author = "Ince, P G and Tomkins, J and Slade, J Y and Thatcher, N M and Shaw, P J",
    	issn = "0022-3069",
    	journal = "Journal of neuropathology and experimental neurology",
    	keywords = "Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: pathology,Brain,Brain: pathology,Female,Humans,Inclusion Bodies,Inclusion Bodies: metabolism,Inclusion Bodies: pathology,Male,Microscopy, Confocal,Middle Aged,Motor Neurons,Motor Neurons: pathology,Mutation,Nerve Degeneration,Nerve Degeneration: pathology,Spinal Cord,Spinal Cord: pathology,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "",
    	number = 10,
    	pages = "895--904",
    	pmid = 9786240,
    	title = "{Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/9786240",
    	volume = 57,
    	year = 1998
    }