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  1. Gavin J Daigle, Karthik Krishnamurthy, Nandini Ramesh, Ian Casci, John Monaghan, Kevin McAvoy, Earl W Godfrey, Dianne C Daniel, Edward M Johnson, Zachary Monahan, Frank Shewmaker, Piera Pasinelli and Udai Bhan Pandey.
    Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity.. Acta neuropathologica 131(4):605–20, April 2016.
    Abstract Amyotrophic lateral sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA-binding proteins, have been linked to ALS pathology. Recently, Pur-alpha, a DNA/RNA-binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA-mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics.
    URL, DOI BibTeX

    @article{Daigle2016,
    	abstract = "Amyotrophic lateral sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA-binding proteins, have been linked to ALS pathology. Recently, Pur-alpha, a DNA/RNA-binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA-mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics.",
    	author = "Daigle, J Gavin and Krishnamurthy, Karthik and Ramesh, Nandini and Casci, Ian and Monaghan, John and McAvoy, Kevin and Godfrey, Earl W and Daniel, Dianne C and Johnson, Edward M and Monahan, Zachary and Shewmaker, Frank and Pasinelli, Piera and Pandey, Udai Bhan",
    	doi = "10.1007/s00401-015-1530-0",
    	issn = "1432-0533",
    	journal = "Acta neuropathologica",
    	month = "apr",
    	number = 4,
    	pages = "605--20",
    	pmid = 26728149,
    	title = "{Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26728149",
    	volume = 131,
    	year = 2016
    }
    
  2. Niran Maharjan, Christina Künzli, Kilian Buthey and Smita Saxena.
    C9ORF72 Regulates Stress Granule Formation and Its Deficiency Impairs Stress Granule Assembly, Hypersensitizing Cells to Stress.. Molecular neurobiology, April 2016.
    Abstract Hexanucleotide repeat expansions in the C9ORF72 gene are causally associated with frontotemporal lobar dementia (FTLD) and/or amyotrophic lateral sclerosis (ALS). The physiological function of the normal C9ORF72 protein remains unclear. In this study, we characterized the subcellular localization of C9ORF72 to processing bodies (P-bodies) and its recruitment to stress granules (SGs) upon stress-related stimuli. Gain of function and loss of function experiments revealed that the long isoform of C9ORF72 protein regulates SG assembly. CRISPR/Cas9-mediated knockdown of C9ORF72 completely abolished SG formation, negatively impacted the expression of SG-associated proteins such as TIA-1 and HuR, and accelerated cell death. Loss of C9ORF72 expression further compromised cellular recovery responses after the removal of stress. Additionally, mimicking the pathogenic condition via the expression of hexanucleotide expansion upstream of C9ORF72 impaired the expression of the C9ORF72 protein, caused an abnormal accumulation of RNA foci, and led to the spontaneous formation of SGs. Our study identifies a novel function for normal C9ORF72 in SG assembly and sheds light into how the mutant expansions might impair SG formation and cellular-stress-related adaptive responses.
    URL, DOI BibTeX

    @article{Maharjan2016,
    	abstract = "Hexanucleotide repeat expansions in the C9ORF72 gene are causally associated with frontotemporal lobar dementia (FTLD) and/or amyotrophic lateral sclerosis (ALS). The physiological function of the normal C9ORF72 protein remains unclear. In this study, we characterized the subcellular localization of C9ORF72 to processing bodies (P-bodies) and its recruitment to stress granules (SGs) upon stress-related stimuli. Gain of function and loss of function experiments revealed that the long isoform of C9ORF72 protein regulates SG assembly. CRISPR/Cas9-mediated knockdown of C9ORF72 completely abolished SG formation, negatively impacted the expression of SG-associated proteins such as TIA-1 and HuR, and accelerated cell death. Loss of C9ORF72 expression further compromised cellular recovery responses after the removal of stress. Additionally, mimicking the pathogenic condition via the expression of hexanucleotide expansion upstream of C9ORF72 impaired the expression of the C9ORF72 protein, caused an abnormal accumulation of RNA foci, and led to the spontaneous formation of SGs. Our study identifies a novel function for normal C9ORF72 in SG assembly and sheds light into how the mutant expansions might impair SG formation and cellular-stress-related adaptive responses.",
    	author = {Maharjan, Niran and K\"{u}nzli, Christina and Buthey, Kilian and Saxena, Smita},
    	doi = "10.1007/s12035-016-9850-1",
    	issn = "1559-1182",
    	journal = "Molecular neurobiology",
    	month = "apr",
    	pmid = 27037575,
    	title = "{C9ORF72 Regulates Stress Granule Formation and Its Deficiency Impairs Stress Granule Assembly, Hypersensitizing Cells to Stress.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/27037575",
    	year = 2016
    }
    
  3. Regina Nostramo, Sapna N Varia, Bo Zhang, Megan M Emerson and Paul K Herman.
    The Catalytic Activity of the Ubp3 Deubiquitinating Protease Is Required for Efficient Stress Granule Assembly in Saccharomyces cerevisiae.. Molecular and cellular biology 36(1):173–83, January 2016.
    Abstract The interior of the eukaryotic cell is a highly compartmentalized space containing both membrane-bound organelles and the recently identified nonmembranous ribonucleoprotein (RNP) granules. This study examines in Saccharomyces cerevisiae the assembly of one conserved type of the latter compartment, known as the stress granule. Stress granules form in response to particular environmental cues and have been linked to a variety of human diseases, including amyotrophic lateral sclerosis. To further our understanding of these structures, a candidate genetic screen was employed to identify regulators of stress granule assembly in quiescent cells. These studies identified a ubiquitin-specific protease, Ubp3, as having an essential role in the assembly of these RNP granules. This function was not shared by other members of the Ubp protease family and required Ubp3 catalytic activity as well as its interaction with the cofactor Bre5. Interestingly, the loss of stress granules was correlated with a decrease in the long-term survival of stationary-phase cells. This phenotype is similar to that observed in mutants defective for the formation of a related RNP complex, the Processing body. Altogether, these observations raise the interesting possibility of a general role for these types of cytoplasmic RNP granules in the survival of G0-like resting cells.
    URL, DOI BibTeX

    @article{Nostramo2016a,
    	abstract = "The interior of the eukaryotic cell is a highly compartmentalized space containing both membrane-bound organelles and the recently identified nonmembranous ribonucleoprotein (RNP) granules. This study examines in Saccharomyces cerevisiae the assembly of one conserved type of the latter compartment, known as the stress granule. Stress granules form in response to particular environmental cues and have been linked to a variety of human diseases, including amyotrophic lateral sclerosis. To further our understanding of these structures, a candidate genetic screen was employed to identify regulators of stress granule assembly in quiescent cells. These studies identified a ubiquitin-specific protease, Ubp3, as having an essential role in the assembly of these RNP granules. This function was not shared by other members of the Ubp protease family and required Ubp3 catalytic activity as well as its interaction with the cofactor Bre5. Interestingly, the loss of stress granules was correlated with a decrease in the long-term survival of stationary-phase cells. This phenotype is similar to that observed in mutants defective for the formation of a related RNP complex, the Processing body. Altogether, these observations raise the interesting possibility of a general role for these types of cytoplasmic RNP granules in the survival of G0-like resting cells.",
    	author = "Nostramo, Regina and Varia, Sapna N and Zhang, Bo and Emerson, Megan M and Herman, Paul K",
    	doi = "10.1128/MCB.00609-15",
    	issn = "1098-5549",
    	journal = "Molecular and cellular biology",
    	keywords = "Biocatalysis,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,Endopeptidases,Endopeptidases: metabolism,Organelles,Organelles: metabolism,Protein Processing, Post-Translational,Protein Processing, Post-Translational: physiology,Ribonucleoproteins,Ribonucleoproteins: metabolism,Saccharomyces cerevisiae,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: metabolism,Saccharomyces cerevisiae: enzymology,Saccharomyces cerevisiae: genetics,Stress, Physiological,Stress, Physiological: genetics,Stress, Physiological: physiology",
    	month = "jan",
    	number = 1,
    	pages = "173--83",
    	pmid = 26503781,
    	title = "{The Catalytic Activity of the Ubp3 Deubiquitinating Protease Is Required for Efficient Stress Granule Assembly in Saccharomyces cerevisiae.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26503781",
    	volume = 36,
    	year = 2016
    }
    
  4. Laura MacNair, Shangxi Xiao, Denise Miletic, Mahdi Ghani, Jean-Pierre Julien, Julia Keith, Lorne Zinman, Ekaterina Rogaeva and Janice Robertson.
    MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.. Brain : a journal of neurology 139(Pt 1):86–100, January 2016.
    Abstract Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. Identifying these changes could uncover molecular pathways that underpin motor neuron degeneration. Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a ≥ 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model, identifying DDX58 and MTHFSD as two TDP-43 targets that are misregulated in amyotrophic lateral sclerosis.
    URL, DOI BibTeX

    @article{MacNair2016,
    	abstract = "Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. However, TDP-43 pathology is common to over 95\% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. Identifying these changes could uncover molecular pathways that underpin motor neuron degeneration. Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a ≥ 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model, identifying DDX58 and MTHFSD as two TDP-43 targets that are misregulated in amyotrophic lateral sclerosis.",
    	author = "MacNair, Laura and Xiao, Shangxi and Miletic, Denise and Ghani, Mahdi and Julien, Jean-Pierre and Keith, Julia and Zinman, Lorne and Rogaeva, Ekaterina and Robertson, Janice",
    	doi = "10.1093/brain/awv308",
    	issn = "1460-2156",
    	journal = "Brain : a journal of neurology",
    	month = "jan",
    	number = "Pt 1",
    	pages = "86--100",
    	pmid = 26525917,
    	title = "{MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26525917",
    	volume = 139,
    	year = 2016
    }
    
  5. R Nostramo and P K Herman.
    Deubiquitination and the regulation of stress granule assembly.. Current genetics, 2016.
    Abstract Stress granules (SGs) are evolutionarily conserved ribonucleoprotein (RNP) structures that form in response to a variety of environmental and cellular cues. The presence of these RNP granules has been linked to a number of human diseases, including neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (Li et al., J Cell Biol 201:361-372, 2013; Nonhoff et al., Mol Biol Cell 18:1385-1396, 2007). Understanding how the assembly of these granules is controlled could, therefore, suggest possible routes of therapy for patients afflicted with these conditions. Interestingly, several reports have identified a potential role for protein deubiquitination in the assembly of these RNP granules. In particular, recent work has found that a specific deubiquitinase enzyme, Ubp3, is required for efficient SG formation in S. cerevisiae (Nostramo et al., Mol Cell Biol 36:173-183, 2016). This same enzyme has been linked to SGs in other organisms, including humans and the fission yeast, Schizosaccharomyces pombe (Takahashi et al., Mol Cell Biol 33:815-829, 2013; Wang et al., RNA 18:694-703, 2012). At first glance, these observations suggest that a striking degree of conservation exists for a ubiquitin-based mechanism controlling SG assembly. However, the devil is truly in the details here, as the precise nature of the involvement of this deubiquitinating enzyme seems to vary in each organism. Here, we briefly review these differences and attempt to provide an overarching model for the role of ubiquitin in SG formation.
    URL, DOI BibTeX

    @article{Nostramo2016,
    	abstract = "Stress granules (SGs) are evolutionarily conserved ribonucleoprotein (RNP) structures that form in response to a variety of environmental and cellular cues. The presence of these RNP granules has been linked to a number of human diseases, including neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (Li et al., J Cell Biol 201:361-372, 2013; Nonhoff et al., Mol Biol Cell 18:1385-1396, 2007). Understanding how the assembly of these granules is controlled could, therefore, suggest possible routes of therapy for patients afflicted with these conditions. Interestingly, several reports have identified a potential role for protein deubiquitination in the assembly of these RNP granules. In particular, recent work has found that a specific deubiquitinase enzyme, Ubp3, is required for efficient SG formation in S. cerevisiae (Nostramo et al., Mol Cell Biol 36:173-183, 2016). This same enzyme has been linked to SGs in other organisms, including humans and the fission yeast, Schizosaccharomyces pombe (Takahashi et al., Mol Cell Biol 33:815-829, 2013; Wang et al., RNA 18:694-703, 2012). At first glance, these observations suggest that a striking degree of conservation exists for a ubiquitin-based mechanism controlling SG assembly. However, the devil is truly in the details here, as the precise nature of the involvement of this deubiquitinating enzyme seems to vary in each organism. Here, we briefly review these differences and attempt to provide an overarching model for the role of ubiquitin in SG formation.",
    	author = "Nostramo, R and Herman, P K",
    	doi = "10.1007/s00294-016-0571-9",
    	issn = "1432-0983",
    	journal = "Current genetics",
    	month = "",
    	pmid = 26852120,
    	title = "{Deubiquitination and the regulation of stress granule assembly.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26852120",
    	year = 2016
    }
    
  6. Hilary Bowden and Dorothee Dormann.
    Altered mRNP granule dynamics in FTLD pathogenesis.. Journal of neurochemistry, 2016.
    Abstract In neurons, RNA-binding proteins (RBPs) play a key role in post-transcriptional gene regulation, e.g. alternative splicing, mRNA localization in neurites and local translation upon synaptic stimulation. There is increasing evidence that defective or mislocalized RBPs - and consequently altered mRNA processing - lead to neuronal dysfunction and cause neurodegeneration, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Cytosolic RBP aggregates containing TDP-43 (TAR DNA binding protein of 43 kDa) or FUS (Fused in sarcoma) are a common hallmark of both disorders. There is mounting evidence that translationally silent mRNP granules, such as stress granules or transport granules, play an important role in the formation of these RBP aggregates. These granules are thought to be "catalytic convertors" of RBP aggregation by providing a high local concentration of RBPs. As recently shown in vitro, RBPs that contain a so-called low complexity domain start to "solidify" and eventually aggregate at high protein concentrations. The same may happen in mRNP granules in vivo, leading to "solidified" granules that lose their dynamic properties and ability to fulfill their physiological functions. This may result in a disturbed stress response, altered mRNA transport and local translation, and formation of pathological TDP-43 or FUS aggregates, all of which may contribute to neuronal dysfunction and neurodegeneration. Here, we discuss the general functional properties of these mRNP granules, how their dynamics may be disrupted in FTLD/ALS, e.g. by loss or gain-of-function of TDP-43 and FUS, and how this may contribute to the development of RBP aggregates and neurotoxicity. This article is protected by copyright. All rights reserved.
    URL, DOI BibTeX

    @article{Bowden2016,
    	abstract = {In neurons, RNA-binding proteins (RBPs) play a key role in post-transcriptional gene regulation, e.g. alternative splicing, mRNA localization in neurites and local translation upon synaptic stimulation. There is increasing evidence that defective or mislocalized RBPs - and consequently altered mRNA processing - lead to neuronal dysfunction and cause neurodegeneration, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Cytosolic RBP aggregates containing TDP-43 (TAR DNA binding protein of 43 kDa) or FUS (Fused in sarcoma) are a common hallmark of both disorders. There is mounting evidence that translationally silent mRNP granules, such as stress granules or transport granules, play an important role in the formation of these RBP aggregates. These granules are thought to be "catalytic convertors" of RBP aggregation by providing a high local concentration of RBPs. As recently shown in vitro, RBPs that contain a so-called low complexity domain start to "solidify" and eventually aggregate at high protein concentrations. The same may happen in mRNP granules in vivo, leading to "solidified" granules that lose their dynamic properties and ability to fulfill their physiological functions. This may result in a disturbed stress response, altered mRNA transport and local translation, and formation of pathological TDP-43 or FUS aggregates, all of which may contribute to neuronal dysfunction and neurodegeneration. Here, we discuss the general functional properties of these mRNP granules, how their dynamics may be disrupted in FTLD/ALS, e.g. by loss or gain-of-function of TDP-43 and FUS, and how this may contribute to the development of RBP aggregates and neurotoxicity. This article is protected by copyright. All rights reserved.},
    	author = "Bowden, Hilary and Dormann, Dorothee",
    	doi = "10.1111/jnc.13601",
    	issn = "1471-4159",
    	journal = "Journal of neurochemistry",
    	month = "",
    	pmid = 26938019,
    	title = "{Altered mRNP granule dynamics in FTLD pathogenesis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26938019",
    	year = 2016
    }
    
  7. Alyssa N Coyne, Shizuka B Yamada, Bhavani Bagevalu Siddegowda, Patricia S Estes, Benjamin L Zaepfel, Jeffrey S Johannesmeyer, Donovan B Lockwood, Linh T Pham, Michael P Hart, Joel A Cassel, Brian Freibaum, Ashley V Boehringer, Paul J Taylor, Allen B Reitz, Aaron D Gitler and Daniela C Zarnescu.
    Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation.. Human molecular genetics 24(24):6886–98, December 2015.
    Abstract RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.
    URL, DOI BibTeX

    @article{Coyne2015,
    	abstract = "RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.",
    	author = "Coyne, Alyssa N and Yamada, Shizuka B and Siddegowda, Bhavani Bagevalu and Estes, Patricia S and Zaepfel, Benjamin L and Johannesmeyer, Jeffrey S and Lockwood, Donovan B and Pham, Linh T and Hart, Michael P and Cassel, Joel A and Freibaum, Brian and Boehringer, Ashley V and Taylor, J Paul and Reitz, Allen B and Gitler, Aaron D and Zarnescu, Daniela C",
    	doi = "10.1093/hmg/ddv389",
    	issn = "1460-2083",
    	journal = "Human molecular genetics",
    	month = "dec",
    	number = 24,
    	pages = "6886--98",
    	pmid = 26385636,
    	title = "{Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26385636",
    	volume = 24,
    	year = 2015
    }
    
  8. Ching-Chieh Chou, Olga M Alexeeva, Shizuka Yamada, Amy Pribadi, Yi Zhang, Bi Mo, Kathryn R Williams, Daniela C Zarnescu and Wilfried Rossoll.
    PABPN1 suppresses TDP-43 toxicity in ALS disease models.. Human molecular genetics 24(18):5154–73, September 2015.
    Abstract TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.
    URL, DOI BibTeX

    @article{Chou2015,
    	abstract = "TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.",
    	author = "Chou, Ching-Chieh and Alexeeva, Olga M and Yamada, Shizuka and Pribadi, Amy and Zhang, Yi and Mo, Bi and Williams, Kathryn R and Zarnescu, Daniela C and Rossoll, Wilfried",
    	doi = "10.1093/hmg/ddv238",
    	issn = "1460-2083",
    	journal = "Human molecular genetics",
    	month = "sep",
    	number = 18,
    	pages = "5154--73",
    	pmid = 26130692,
    	title = "{PABPN1 suppresses TDP-43 toxicity in ALS disease models.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26130692",
    	volume = 24,
    	year = 2015
    }
    
  9. Emma L Scotter, Han-Jou Chen and Christopher E Shaw.
    TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 12(2):352–63, April 2015.
    Abstract Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia.
    URL, DOI BibTeX

    @article{Scotter2015,
    	abstract = "Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia.",
    	author = "Scotter, Emma L and Chen, Han-Jou and Shaw, Christopher E",
    	doi = "10.1007/s13311-015-0338-x",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scotter, Chen, Shaw - 2015 - TDP-43 Proteinopathy and ALS Insights into Disease Mechanisms and Therapeutic Targets.pdf:pdf",
    	issn = "1878-7479",
    	journal = "Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: therapy,Animals,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Environment,Gene Silencing,Gene Silencing: physiology,Humans,Mutation,Mutation: genetics,TDP-43 Proteinopathies,TDP-43 Proteinopathies: genetics,TDP-43 Proteinopathies: metabolism,TDP-43 Proteinopathies: therapy",
    	month = "apr",
    	number = 2,
    	pages = "352--63",
    	pmid = 25652699,
    	title = "{TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4404432\&tool=pmcentrez\&rendertype=abstract",
    	volume = 12,
    	year = 2015
    }
    
  10. Aditi, Andrew W Folkmann and Susan R Wente.
    Cytoplasmic hGle1A regulates stress granules by modulation of translation.. Molecular biology of the cell 26(8):1476–90, April 2015.
    Abstract When eukaryotic cells respond to stress, gene expression pathways change to selectively export and translate subsets of mRNAs. Translationally repressed mRNAs accumulate in cytoplasmic foci known as stress granules (SGs). SGs are in dynamic equilibrium with the translational machinery, but mechanisms controlling this are unclear. Gle1 is required for DEAD-box protein function during mRNA export and translation. We document that human Gle1 (hGle1) is a critical regulator of translation during stress. hGle1 is recruited to SGs, and hGLE1 small interfering RNA-mediated knockdown perturbs SG assembly, resulting in increased numbers of smaller SGs. The rate of SG disassembly is also delayed. Furthermore, SG hGle1-depletion defects correlate with translation perturbations, and the hGle1 role in SGs is independent of mRNA export. Interestingly, we observe isoform-specific roles for hGle1 in which SG function requires hGle1A, whereas mRNA export requires hGle1B. We find that the SG defects in hGle1-depleted cells are rescued by puromycin or DDX3 expression. Together with recent links of hGLE1 mutations in amyotrophic lateral sclerosis patients, these results uncover a paradigm for hGle1A modulating the balance between translation and SGs during stress and disease.
    URL, DOI BibTeX

    @article{Aditi2015,
    	abstract = "When eukaryotic cells respond to stress, gene expression pathways change to selectively export and translate subsets of mRNAs. Translationally repressed mRNAs accumulate in cytoplasmic foci known as stress granules (SGs). SGs are in dynamic equilibrium with the translational machinery, but mechanisms controlling this are unclear. Gle1 is required for DEAD-box protein function during mRNA export and translation. We document that human Gle1 (hGle1) is a critical regulator of translation during stress. hGle1 is recruited to SGs, and hGLE1 small interfering RNA-mediated knockdown perturbs SG assembly, resulting in increased numbers of smaller SGs. The rate of SG disassembly is also delayed. Furthermore, SG hGle1-depletion defects correlate with translation perturbations, and the hGle1 role in SGs is independent of mRNA export. Interestingly, we observe isoform-specific roles for hGle1 in which SG function requires hGle1A, whereas mRNA export requires hGle1B. We find that the SG defects in hGle1-depleted cells are rescued by puromycin or DDX3 expression. Together with recent links of hGLE1 mutations in amyotrophic lateral sclerosis patients, these results uncover a paradigm for hGle1A modulating the balance between translation and SGs during stress and disease.",
    	author = "Aditi and Folkmann, Andrew W and Wente, Susan R",
    	doi = "10.1091/mbc.E14-11-1523",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Aditi, Folkmann, Wente - 2015 - Cytoplasmic hGle1A regulates stress granules by modulation of translation.pdf:pdf",
    	issn = "1939-4586",
    	journal = "Molecular biology of the cell",
    	keywords = "Cell Line,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,Down-Regulation,Humans,Nucleocytoplasmic Transport Proteins,Nucleocytoplasmic Transport Proteins: genetics,Nucleocytoplasmic Transport Proteins: metabolism,Protein Biosynthesis,Protein Biosynthesis: physiology,Protein Isoforms,Protein Isoforms: metabolism,Stress, Physiological",
    	month = "apr",
    	number = 8,
    	pages = "1476--90",
    	pmid = 25694449,
    	title = "{Cytoplasmic hGle1A regulates stress granules by modulation of translation.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4395128\&tool=pmcentrez\&rendertype=abstract",
    	volume = 26,
    	year = 2015
    }
    
  11. Jessica Lenzi, Riccardo De Santis, Valeria Turris, Mariangela Morlando, Pietro Laneve, Andrea Calvo, Virginia Caliendo, Adriano Chiò, Alessandro Rosa and Irene Bozzoni.
    ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons.. Disease models & mechanisms 8(7):755–66, 2015.
    Abstract Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUS(R514S) and FUS(R521C) patient fibroblasts, whereas in the case of the severe FUS(P525L) mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis.
    URL, DOI BibTeX

    @article{Lenzi2015,
    	abstract = "Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUS(R514S) and FUS(R521C) patient fibroblasts, whereas in the case of the severe FUS(P525L) mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis.",
    	author = "Lenzi, Jessica and {De Santis}, Riccardo and de Turris, Valeria and Morlando, Mariangela and Laneve, Pietro and Calvo, Andrea and Caliendo, Virginia and Chi\`{o}, Adriano and Rosa, Alessandro and Bozzoni, Irene",
    	doi = "10.1242/dmm.020099",
    	issn = "1754-8411",
    	journal = "Disease models \& mechanisms",
    	keywords = "Active Transport, Cell Nucleus,Amino Acid Substitution,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Cell Differentiation,Cell Line,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,Cytoplasmic Granules: pathology,Humans,Induced Pluripotent Stem Cells,Induced Pluripotent Stem Cells: metabolism,Induced Pluripotent Stem Cells: pathology,Models, Neurological,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Mutagenesis, Site-Directed,Mutant Proteins,Mutant Proteins: genetics,Mutant Proteins: metabolism,RNA-Binding Protein FUS,RNA-Binding Protein FUS: genetics,RNA-Binding Protein FUS: metabolism,Spinal Cord,Spinal Cord: metabolism,Spinal Cord: pathology,Stress, Physiological",
    	month = "",
    	number = 7,
    	pages = "755--66",
    	pmid = 26035390,
    	title = "{ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4486861\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2015
    }
    
  12. Anna Emde, Chen Eitan, Lee-Loung Liou, Ryan T Libby, Natali Rivkin, Iddo Magen, Irit Reichenstein, Hagar Oppenheim, Raya Eilam, Aurelio Silvestroni, Betty Alajajian, Iddo Z Ben-Dov, Julianne Aebischer, Alon Savidor, Yishai Levin, Robert Sons, Scott M Hammond, John M Ravits, Thomas Möller and Eran Hornstein.
    Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS.. The EMBO journal 34(21):2633–51, 2015.
    Abstract Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.
    URL, DOI BibTeX

    @article{Emde2015,
    	abstract = "Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.",
    	author = {Emde, Anna and Eitan, Chen and Liou, Lee-Loung and Libby, Ryan T and Rivkin, Natali and Magen, Iddo and Reichenstein, Irit and Oppenheim, Hagar and Eilam, Raya and Silvestroni, Aurelio and Alajajian, Betty and Ben-Dov, Iddo Z and Aebischer, Julianne and Savidor, Alon and Levin, Yishai and Sons, Robert and Hammond, Scott M and Ravits, John M and M\"{o}ller, Thomas and Hornstein, Eran},
    	doi = "10.15252/embj.201490493",
    	issn = "1460-2075",
    	journal = "The EMBO journal",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: pathology,Animals,Base Sequence,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,DEAD-box RNA Helicases,DEAD-box RNA Helicases: metabolism,Down-Regulation,Drug Evaluation, Preclinical,Enoxacin,Enoxacin: pharmacology,Female,HEK293 Cells,Humans,Male,Mice, Inbred C57BL,Mice, Transgenic,MicroRNAs,MicroRNAs: biosynthesis,MicroRNAs: genetics,Motor Neurons,Motor Neurons: metabolism,RNA Interference,RNA Processing, Post-Transcriptional,Ribonuclease III,Ribonuclease III: metabolism,Stress, Physiological,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "",
    	number = 21,
    	pages = "2633--51",
    	pmid = 26330466,
    	title = "{Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26330466",
    	volume = 34,
    	year = 2015
    }
    
  13. Amandine Molliex, Jamshid Temirov, Jihun Lee, Maura Coughlin, Anderson P Kanagaraj, Hong Joo Kim, Tanja Mittag and Paul J Taylor.
    Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.. Cell 163(1):123–33, 2015.
    Abstract Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.
    URL, DOI BibTeX

    @article{Molliex2015,
    	abstract = "Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.",
    	author = "Molliex, Amandine and Temirov, Jamshid and Lee, Jihun and Coughlin, Maura and Kanagaraj, Anderson P and Kim, Hong Joo and Mittag, Tanja and Taylor, J Paul",
    	doi = "10.1016/j.cell.2015.09.015",
    	issn = "1097-4172",
    	journal = "Cell",
    	keywords = "Amyloid,Amyloid: metabolism,Cell Line, Tumor,Cytoplasmic Granules,Cytoplasmic Granules: chemistry,Cytoplasmic Granules: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: chemistry,DNA-Binding Proteins: metabolism,HeLa Cells,Heterogeneous-Nuclear Ribonucleoprotein Group A-B,Heterogeneous-Nuclear Ribonucleoprotein Group A-B:,Humans,Protein Aggregation, Pathological,Protein Aggregation, Pathological: metabolism",
    	month = "",
    	number = 1,
    	pages = "123--33",
    	pmid = 26406374,
    	title = "{Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26406374",
    	volume = 163,
    	year = 2015
    }
    
  14. Yang Li, Mahlon Collins, Rachel Geiser, Nadine Bakkar, David Riascos and Robert Bowser.
    RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules.. Scientific reports 5:14262, January 2015.
    Abstract The aggregation of RNA-binding proteins is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBM45 is an RNA-binding protein that forms cytoplasmic inclusions in neurons and glia in ALS and FTLD. To explore the role of RBM45 in ALS and FTLD, we examined the contribution of the protein's domains to its function, subcellular localization, and interaction with itself and ALS-linked proteins. We find that RBM45 forms homo-oligomers and physically associates with the ALS-linked proteins TDP-43 and FUS in the nucleus. Nuclear localization of RBM45 is mediated by a bipartite nuclear-localization sequence (NLS) located at the C-terminus. RBM45 mutants that lack a functional NLS accumulate in the cytoplasm and form TDP-43 positive stress granules. Moreover, we identify a novel structural element, termed the homo-oligomer assembly (HOA) domain, that is highly conserved across species and promote homo-oligomerization of RBM45. RBM45 mutants that fail to form homo-oligomers exhibit significantly reduced association with ALS-linked proteins and inclusion into stress granules. These results show that RMB45 may function as a homo-oligomer and that its oligomerization contributes to ALS/FTLD RNA-binding protein aggregation.
    URL, DOI BibTeX

    @article{Li2015,
    	abstract = "The aggregation of RNA-binding proteins is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBM45 is an RNA-binding protein that forms cytoplasmic inclusions in neurons and glia in ALS and FTLD. To explore the role of RBM45 in ALS and FTLD, we examined the contribution of the protein's domains to its function, subcellular localization, and interaction with itself and ALS-linked proteins. We find that RBM45 forms homo-oligomers and physically associates with the ALS-linked proteins TDP-43 and FUS in the nucleus. Nuclear localization of RBM45 is mediated by a bipartite nuclear-localization sequence (NLS) located at the C-terminus. RBM45 mutants that lack a functional NLS accumulate in the cytoplasm and form TDP-43 positive stress granules. Moreover, we identify a novel structural element, termed the homo-oligomer assembly (HOA) domain, that is highly conserved across species and promote homo-oligomerization of RBM45. RBM45 mutants that fail to form homo-oligomers exhibit significantly reduced association with ALS-linked proteins and inclusion into stress granules. These results show that RMB45 may function as a homo-oligomer and that its oligomerization contributes to ALS/FTLD RNA-binding protein aggregation.",
    	author = "Li, Yang and Collins, Mahlon and Geiser, Rachel and Bakkar, Nadine and Riascos, David and Bowser, Robert",
    	doi = "10.1038/srep14262",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Li et al. - 2015 - RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules.pdf:pdf",
    	issn = "2045-2322",
    	journal = "Scientific reports",
    	month = "jan",
    	pages = 14262,
    	pmid = 26391765,
    	title = "{RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4585734\&tool=pmcentrez\&rendertype=abstract",
    	volume = 5,
    	year = 2015
    }
    
  15. Ana\"ıs Aulas and Christine Vande Velde.
    Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS?. Frontiers in cellular neuroscience 9:423, January 2015.
    Abstract Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.
    URL, DOI BibTeX

    @article{Aulas2015,
    	abstract = "Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.",
    	author = {Aulas, Ana\"{\i}s and {Vande Velde}, Christine},
    	doi = "10.3389/fncel.2015.00423",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Aulas, Vande Velde - 2015 - Alterations in stress granule dynamics driven by TDP-43 and FUS a link to pathological inclusions in ALS.pdf:pdf",
    	issn = "1662-5102",
    	journal = "Frontiers in cellular neuroscience",
    	month = "jan",
    	pages = 423,
    	pmid = 26557057,
    	title = "{Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS?}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4615823\&tool=pmcentrez\&rendertype=abstract",
    	volume = 9,
    	year = 2015
    }
    
  16. Hyun-Hee Ryu, Mi-Hee Jun, Kyung-Jin Min, Deok-Jin Jang, Yong-Seok Lee, Hyong Kyu Kim and Jin-A Lee.
    Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons.. Neurobiology of aging 35(12):2822–31, December 2014.
    Abstract Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal neurodegenerative disease that causes progressive muscular weakness and has overlapping clinical and pathologic characteristics with frontotemporal lobar degeneration. However, the role of autophagy in regulation of FUS-positive stress granules (SGs) and aggregates remains unclear. We found that the ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under oxidative stress, leading to a disruption in the release of FUS from SGs in cultured neurons. Autophagy controls the quality of proteins or organelles; therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs. Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5(-/-) mouse embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However, FUS(R521C) expression did not significantly impair autophagic degradation. Moreover, autophagy activation with rapamycin reduced the accumulation of FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced neurite fragmentation and cell death in neurons expressing mutant FUS under oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS associated with a FUS mutation under oxidative stress, as well as therapeutic insight regarding FUS pathology associated with excessive SGs.
    URL, DOI BibTeX

    @article{Ryu2014,
    	abstract = "Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal neurodegenerative disease that causes progressive muscular weakness and has overlapping clinical and pathologic characteristics with frontotemporal lobar degeneration. However, the role of autophagy in regulation of FUS-positive stress granules (SGs) and aggregates remains unclear. We found that the ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under oxidative stress, leading to a disruption in the release of FUS from SGs in cultured neurons. Autophagy controls the quality of proteins or organelles; therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs. Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5(-/-) mouse embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However, FUS(R521C) expression did not significantly impair autophagic degradation. Moreover, autophagy activation with rapamycin reduced the accumulation of FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced neurite fragmentation and cell death in neurons expressing mutant FUS under oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS associated with a FUS mutation under oxidative stress, as well as therapeutic insight regarding FUS pathology associated with excessive SGs.",
    	author = "Ryu, Hyun-Hee and Jun, Mi-Hee and Min, Kyung-Jin and Jang, Deok-Jin and Lee, Yong-Seok and Kim, Hyong Kyu and Lee, Jin-A",
    	doi = "10.1016/j.neurobiolaging.2014.07.026",
    	issn = "1558-1497",
    	journal = "Neurobiology of aging",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: pathology,Animals,Autophagy,Autophagy: drug effects,Autophagy: physiology,Cells, Cultured,Cytoplasmic Granules,Cytoplasmic Granules: genetics,Cytoplasmic Granules: pathology,Female,Frontotemporal Lobar Degeneration,Frontotemporal Lobar Degeneration: genetics,Frontotemporal Lobar Degeneration: pathology,Gene Expression Regulation,Genetic Association Studies,Humans,Male,Mice,Mutation,Neurons,Neurons: cytology,Neurons: metabolism,Neurons: pathology,Oxidative Stress,Oxidative Stress: genetics,Oxidative Stress: physiology,RNA-Binding Protein FUS,RNA-Binding Protein FUS: genetics,RNA-Binding Protein FUS: metabolism,Sirolimus,Sirolimus: pharmacology",
    	month = "dec",
    	number = 12,
    	pages = "2822--31",
    	pmid = 25216585,
    	title = "{Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25216585",
    	volume = 35,
    	year = 2014
    }
    
  17. Benjamin Wolozin.
    Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease.. Discovery medicine 17(91):47–52, 2014.
    Abstract Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.
    URL BibTeX

    @article{Wolozin2014,
    	abstract = "Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.",
    	author = "Wolozin, Benjamin",
    	issn = "1944-7930",
    	journal = "Discovery medicine",
    	month = "",
    	number = 91,
    	pages = "47--52",
    	pmid = 24411700,
    	title = "{Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24411700",
    	volume = 17,
    	year = 2014
    }
    
  18. Yun R Li, Oliver D King, James Shorter and Aaron D Gitler.
    Stress granules as crucibles of ALS pathogenesis.. The Journal of cell biology 201(3):361–72, 2013.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.
    URL, DOI BibTeX

    @article{Li2013,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.",
    	author = "Li, Yun R and King, Oliver D and Shorter, James and Gitler, Aaron D",
    	doi = "10.1083/jcb.201302044",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Li et al. - 2013 - Stress granules as crucibles of ALS pathogenesis.pdf:pdf",
    	issn = "1540-8140",
    	journal = "The Journal of cell biology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Environmental Exposure,Humans,Nerve Tissue Proteins,Nerve Tissue Proteins: metabolism,Prions,Prions: metabolism,Protein Structure, Tertiary,RNA-Binding Protein FUS,RNA-Binding Protein FUS: metabolism,Stress, Physiological",
    	month = "",
    	number = 3,
    	pages = "361--72",
    	pmid = 23629963,
    	title = "{Stress granules as crucibles of ALS pathogenesis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3639398\&tool=pmcentrez\&rendertype=abstract",
    	volume = 201,
    	year = 2013
    }
    
  19. Benjamin Wolozin.
    Regulated protein aggregation: stress granules and neurodegeneration.. Molecular neurodegeneration 7:56, January 2012.
    Abstract The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation of stress granules. Stress granules assemble when RNA binding proteins aggregate through their glycine rich domains. Stress granules function to sequester, silence and/or degrade RNA transcripts as part of a mechanism that adapts patterns of local RNA translation to facilitate the stress response. Aggregation of RNA binding proteins is reversible and is tightly regulated through pathways, such as phosphorylation of elongation initiation factor 2$\alpha$. Microtubule associated protein tau also appears to regulate stress granule formation. Conversely, stress granule formation stimulates pathological changes associated with tau. In this review, I propose that the aggregation of many pathological, intracellular proteins, including TDP-43, FUS or tau, proceeds through the stress granule pathway. Mutations in genes coding for stress granule associated proteins or prolonged physiological stress, lead to enhanced stress granule formation, which accelerates the pathophysiology of protein aggregation in neurodegenerative diseases. Over-active stress granule formation could act to sequester functional RNA binding proteins and/or interfere with mRNA transport and translation, each of which might potentiate neurodegeneration. The reversibility of the stress granule pathway also offers novel opportunities to stimulate endogenous biochemical pathways to disaggregate these pathological stress granules, and perhaps delay the progression of disease.
    URL, DOI BibTeX

    @article{Wolozin2012,
    	abstract = "The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation of stress granules. Stress granules assemble when RNA binding proteins aggregate through their glycine rich domains. Stress granules function to sequester, silence and/or degrade RNA transcripts as part of a mechanism that adapts patterns of local RNA translation to facilitate the stress response. Aggregation of RNA binding proteins is reversible and is tightly regulated through pathways, such as phosphorylation of elongation initiation factor 2$\alpha$. Microtubule associated protein tau also appears to regulate stress granule formation. Conversely, stress granule formation stimulates pathological changes associated with tau. In this review, I propose that the aggregation of many pathological, intracellular proteins, including TDP-43, FUS or tau, proceeds through the stress granule pathway. Mutations in genes coding for stress granule associated proteins or prolonged physiological stress, lead to enhanced stress granule formation, which accelerates the pathophysiology of protein aggregation in neurodegenerative diseases. Over-active stress granule formation could act to sequester functional RNA binding proteins and/or interfere with mRNA transport and translation, each of which might potentiate neurodegeneration. The reversibility of the stress granule pathway also offers novel opportunities to stimulate endogenous biochemical pathways to disaggregate these pathological stress granules, and perhaps delay the progression of disease.",
    	author = "Wolozin, Benjamin",
    	doi = "10.1186/1750-1326-7-56",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wolozin - 2012 - Regulated protein aggregation stress granules and neurodegeneration.pdf:pdf",
    	issn = "1750-1326",
    	journal = "Molecular neurodegeneration",
    	keywords = "Animals,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,Humans,Nerve Degeneration,Nerve Degeneration: metabolism,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Neurodegenerative Diseases: pathology,Proteins,Proteins: chemistry,Proteins: metabolism,RNA-Binding Proteins,RNA-Binding Proteins: metabolism,Stress, Physiological,Stress, Physiological: physiology",
    	month = "jan",
    	pages = 56,
    	pmid = 23164372,
    	title = "{Regulated protein aggregation: stress granules and neurodegeneration.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3519755\&tool=pmcentrez\&rendertype=abstract",
    	volume = 7,
    	year = 2012
    }
    
  20. Natalie Gilks, Nancy Kedersha, Maranatha Ayodele, Lily Shen, Georg Stoecklin, Laura M Dember and Paul Anderson.
    Stress granule assembly is mediated by prion-like aggregation of TIA-1.. Molecular biology of the cell 15(12):5383–98, 2004.
    Abstract TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.
    URL, DOI BibTeX

    @article{Gilks2004,
    	abstract = "TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.",
    	author = "Gilks, Natalie and Kedersha, Nancy and Ayodele, Maranatha and Shen, Lily and Stoecklin, Georg and Dember, Laura M and Anderson, Paul",
    	doi = "10.1091/mbc.E04-08-0715",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gilks et al. - 2004 - Stress granule assembly is mediated by prion-like aggregation of TIA-1.pdf:pdf",
    	issn = "1059-1524",
    	journal = "Molecular biology of the cell",
    	keywords = "Amino Acid Sequence,Animals,COS Cells,Cercopithecus aethiops,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,Gene Expression Regulation,HSP70 Heat-Shock Proteins,HSP70 Heat-Shock Proteins: genetics,HSP70 Heat-Shock Proteins: metabolism,Humans,Inclusion Bodies,Inclusion Bodies: metabolism,Mice,Microscopy, Electron, Transmission,Molecular Sequence Data,Peptide Hydrolases,Peptide Hydrolases: metabolism,Prions,Prions: chemistry,Protein Binding,RNA-Binding Proteins,RNA-Binding Proteins: chemistry,RNA-Binding Proteins: genetics,RNA-Binding Proteins: metabolism,Ribosomes,Ribosomes: metabolism,Solubility",
    	month = "",
    	number = 12,
    	pages = "5383--98",
    	pmid = 15371533,
    	title = "{Stress granule assembly is mediated by prion-like aggregation of TIA-1.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=532018\&tool=pmcentrez\&rendertype=abstract",
    	volume = 15,
    	year = 2004
    }