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  1. D R Sharma, W Y Wani, A Sunkaria, R J Kandimalla, R K Sharma, D Verma, A Bal and K D Gill.
    Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.. Neuroscience 324:163–76, 2016.
    Abstract Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10mg/kg body wt/day) reduced aluminum (10mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.
    URL, DOI BibTeX

    @article{Sharma2016,
    	abstract = "Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10mg/kg body wt/day) reduced aluminum (10mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H\&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.",
    	author = "Sharma, D R and Wani, W Y and Sunkaria, A and Kandimalla, R J and Sharma, R K and Verma, D and Bal, A and Gill, K D",
    	doi = "10.1016/j.neuroscience.2016.02.055",
    	issn = "1873-7544",
    	journal = "Neuroscience",
    	month = "",
    	pages = "163--76",
    	pmid = 26944603,
    	title = "{Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26944603",
    	volume = 324,
    	year = 2016
    }
    
  2. Liang Zhou, Hongfeng Wang, Haigang Ren, Qingsong Hu, Zheng Ying and Guanghui Wang.
    Bcl-2 Decreases the Affinity of SQSTM1/p62 to Poly-Ubiquitin Chains and Suppresses the Aggregation of Misfolded Protein in Neurodegenerative Disease.. Molecular neurobiology 52(3):1180–9, 2015.
    Abstract Poly-ubiquitinated protein aggregate formation is the most striking hallmark of various neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Mutations of many ubiquitin-associated proteins involved in the regulation of protein aggregation, such as SQSTM1/p62 (p62), parkin, and VCP, are closely linked to neurodegeneration. B-cell lymphoma 2 (Bcl-2) is a key regulator in autophagy, apoptosis, and mitochondria quality control in many cell types including neurons, and it plays important roles in the pathogenesis of neurodegenerative diseases mentioned above. Our previous work showed that Bcl-2 can directly bind to p62, and here we report that Bcl-2 directly interacts with the N-terminus of p62, but not the C-terminus (UBA domain). Interestingly and importantly, Bcl-2 affects the affinity of p62 to poly-ubiquitin chains and suppresses the aggregation of poly-ubiquitinated proteins such as mutant huntingtin associated with Huntington's disease. Our study reveals a role of Bcl-2 that involves in the regulation of misfolded proteins.
    URL, DOI BibTeX

    @article{Zhou2015,
    	abstract = "Poly-ubiquitinated protein aggregate formation is the most striking hallmark of various neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Mutations of many ubiquitin-associated proteins involved in the regulation of protein aggregation, such as SQSTM1/p62 (p62), parkin, and VCP, are closely linked to neurodegeneration. B-cell lymphoma 2 (Bcl-2) is a key regulator in autophagy, apoptosis, and mitochondria quality control in many cell types including neurons, and it plays important roles in the pathogenesis of neurodegenerative diseases mentioned above. Our previous work showed that Bcl-2 can directly bind to p62, and here we report that Bcl-2 directly interacts with the N-terminus of p62, but not the C-terminus (UBA domain). Interestingly and importantly, Bcl-2 affects the affinity of p62 to poly-ubiquitin chains and suppresses the aggregation of poly-ubiquitinated proteins such as mutant huntingtin associated with Huntington's disease. Our study reveals a role of Bcl-2 that involves in the regulation of misfolded proteins.",
    	author = "Zhou, Liang and Wang, Hongfeng and Ren, Haigang and Hu, Qingsong and Ying, Zheng and Wang, Guanghui",
    	doi = "10.1007/s12035-014-8908-1",
    	issn = "1559-1182",
    	journal = "Molecular neurobiology",
    	month = "",
    	number = 3,
    	pages = "1180--9",
    	pmid = 25311206,
    	title = "{Bcl-2 Decreases the Affinity of SQSTM1/p62 to Poly-Ubiquitin Chains and Suppresses the Aggregation of Misfolded Protein in Neurodegenerative Disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25311206",
    	volume = 52,
    	year = 2015
    }
    
  3. R Mutihac, J Alegre-Abarrategui, D Gordon, L Farrimond, M Yamasaki-Mann, K Talbot and R Wade-Martins.
    TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca²⁺ signaling in motor neurons.. Neurobiology of disease 75:64–77, 2015.
    Abstract The transactive response DNA binding protein (TDP-43) is a major component of the characteristic neuronal cytoplasmic inclusions seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Furthermore, pathogenic mutations in the gene encoding TDP-43, TARDBP, are found in sporadic and familial ALS cases. To study the molecular mechanisms of cellular toxicity due to TDP-43 mutations we generated a novel in vitro cellular model using a fluorescently tagged human genomic TARDBP locus carrying one of two ALS-associated mutations, A382T or M337V, which were used to generate site-specific bacterial artificial chromosome (BAC) human stable cell lines and BAC transgenic mice. In cell lines and primary motor neurons in culture, TDP-M337V mislocalized to the cytoplasm more frequently than wild-type TDP (wt-TDP) and TDP-A382T, an effect potentiated by oxidative stress. Expression of mutant TDP-M337V correlated with increased apoptosis detected by cleaved caspase-3 staining. Cells expressing mislocalized TDP-M337V spontaneously developed cytoplasmic aggregates, while for TDP-A382T aggregates were only revealed after endoplasmic reticulum (ER) stress induced by the calcium-modifying drug thapsigargin. Lowering Ca(2+) concentration in the ER of wt-TDP cells partially recapitulated the effect of pathogenic mutations by increasing TDP-43 cytoplasmic mislocalization, suggesting Ca(2+) dysregulation as a potential mediator of pathology through alterations in Bcl-2 protein levels. Ca(2+) signaling from the ER was impaired in immortalized cells and primary neurons carrying TDP-43 mutations, with a 50% reduction in the levels of luminal ER Ca(2+) stores content and delayed Ca(2+) release compared with cells carrying wt-TDP. The deficits in Ca(2+) release in human cells correlated with the upregulation of Bcl-2 and siRNA-mediated knockdown of Bcl-2 restored the amplitude of Ca(2+) oscillations in TDP-M337V cells. These results suggest that TDP-43 pathogenic mutations elicit cytoplasmic mislocalization of TDP-43 and Bcl-2 mediated ER Ca(2+) signaling dysregulation.
    URL, DOI BibTeX

    @article{Mutihac2015,
    	abstract = "The transactive response DNA binding protein (TDP-43) is a major component of the characteristic neuronal cytoplasmic inclusions seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Furthermore, pathogenic mutations in the gene encoding TDP-43, TARDBP, are found in sporadic and familial ALS cases. To study the molecular mechanisms of cellular toxicity due to TDP-43 mutations we generated a novel in vitro cellular model using a fluorescently tagged human genomic TARDBP locus carrying one of two ALS-associated mutations, A382T or M337V, which were used to generate site-specific bacterial artificial chromosome (BAC) human stable cell lines and BAC transgenic mice. In cell lines and primary motor neurons in culture, TDP-M337V mislocalized to the cytoplasm more frequently than wild-type TDP (wt-TDP) and TDP-A382T, an effect potentiated by oxidative stress. Expression of mutant TDP-M337V correlated with increased apoptosis detected by cleaved caspase-3 staining. Cells expressing mislocalized TDP-M337V spontaneously developed cytoplasmic aggregates, while for TDP-A382T aggregates were only revealed after endoplasmic reticulum (ER) stress induced by the calcium-modifying drug thapsigargin. Lowering Ca(2+) concentration in the ER of wt-TDP cells partially recapitulated the effect of pathogenic mutations by increasing TDP-43 cytoplasmic mislocalization, suggesting Ca(2+) dysregulation as a potential mediator of pathology through alterations in Bcl-2 protein levels. Ca(2+) signaling from the ER was impaired in immortalized cells and primary neurons carrying TDP-43 mutations, with a 50\% reduction in the levels of luminal ER Ca(2+) stores content and delayed Ca(2+) release compared with cells carrying wt-TDP. The deficits in Ca(2+) release in human cells correlated with the upregulation of Bcl-2 and siRNA-mediated knockdown of Bcl-2 restored the amplitude of Ca(2+) oscillations in TDP-M337V cells. These results suggest that TDP-43 pathogenic mutations elicit cytoplasmic mislocalization of TDP-43 and Bcl-2 mediated ER Ca(2+) signaling dysregulation.",
    	author = "Mutihac, R and Alegre-Abarrategui, J and Gordon, D and Farrimond, L and Yamasaki-Mann, M and Talbot, K and Wade-Martins, R",
    	doi = "10.1016/j.nbd.2014.12.010",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	keywords = "Animals,Apoptosis,Apoptosis: physiology,Calcium,Calcium: metabolism,Caspase 3,Caspase 3: metabolism,Cells, Cultured,Chromosomes, Artificial, Bacterial,Cytoplasm,Cytoplasm: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Endoplasmic Reticulum,Endoplasmic Reticulum: metabolism,HEK293 Cells,Humans,Mice, Transgenic,Motor Neurons,Motor Neurons: metabolism,Mutation, Missense,Oxidative Stress,Oxidative Stress: physiology,Proto-Oncogene Proteins c-bcl-2,Proto-Oncogene Proteins c-bcl-2: genetics,Proto-Oncogene Proteins c-bcl-2: metabolism,Spinal Cord,Spinal Cord: metabolism",
    	month = "",
    	pages = "64--77",
    	pmid = 25526708,
    	title = "{TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca²⁺ signaling in motor neurons.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25526708",
    	volume = 75,
    	year = 2015
    }
    
  4. Zachary Macchi, Yunxia Wang, Dan Moore, Jonathan Katz, David Saperstein, David Walk, Ericka Simpson, Angela Genge, Tulio Bertorini, Americo J Fernandes, Andrea Swenson, Lauren Elman, Mazen Dimachkie, Laura Herbelin, Joann Miller, Jianghua Lu, Heather Wilkins, Russell H Swerdlow, Jeffrey Statland and Richard Barohn.
    A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement.. Amyotrophic lateral sclerosis & frontotemporal degeneration 16(5-6):345–52, 2015.
    Abstract {Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92
    URL, DOI BibTeX

    @article{Macchi2015,
    	abstract = "{Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1\%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92",
    	p = "",
    	author = "Macchi, Zachary and Wang, Yunxia and Moore, Dan and Katz, Jonathan and Saperstein, David and Walk, David and Simpson, Ericka and Genge, Angela and Bertorini, Tulio and Fernandes, J Americo and Swenson, Andrea and Elman, Lauren and Dimachkie, Mazen and Herbelin, Laura and Miller, Joann and Lu, Jianghua and Wilkins, Heather and Swerdlow, Russell H and Statland, Jeffrey and Barohn, Richard",
    	doi = "10.3109/21678421.2015.1026826",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Macchi et al. - 2015 - A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis Possible mitochondria.pdf:pdf",
    	issn = "2167-9223",
    	journal = "Amyotrophic lateral sclerosis \& frontotemporal degeneration",
    	month = "",
    	number = "5-6",
    	pages = "345--52",
    	pmid = 25832828,
    	title = "{A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4610861\&tool=pmcentrez\&rendertype=abstract",
    	volume = 16,
    	year = 2015
    }
    
  5. S-Y Wang, M Ren, H-Z Jiang, J Wang, H-Q Jiang, X Yin, Y Qi, X-D Wang, G-T Dong, T-H Wang, Y-Q Yang and H-L Feng.
    Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate.. Neuroscience 301:276–88, 2015.
    Abstract Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.
    URL, DOI BibTeX

    @article{Wang2015,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.",
    	author = "Wang, S-Y and Ren, M and Jiang, H-Z and Wang, J and Jiang, H-Q and Yin, X and Qi, Y and Wang, X-D and Dong, G-T and Wang, T-H and Yang, Y-Q and Feng, H-L",
    	doi = "10.1016/j.neuroscience.2015.06.002",
    	issn = "1873-7544",
    	journal = "Neuroscience",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: genetics,Animals,Cells, Cultured,Disease Models, Animal,Embryo, Mammalian,Gene Expression Regulation,Gene Expression Regulation: drug effects,Gene Expression Regulation: genetics,Humans,Lithium Chloride,Lithium Chloride: therapeutic use,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: metabolism,Neuroprotective Agents,Neuroprotective Agents: therapeutic use,RNA, Small Interfering,RNA, Small Interfering: genetics,RNA, Small Interfering: metabolism,Receptors, Notch,Receptors, Notch: metabolism,Signal Transduction,Signal Transduction: drug effects,Spinal Cord,Spinal Cord: cytology,Superoxide Dismutase,Superoxide Dismutase: genetics,Transfection,Valproic Acid,Valproic Acid: therapeutic use",
    	month = "",
    	pages = "276--88",
    	pmid = 26067594,
    	title = "{Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26067594",
    	volume = 301,
    	year = 2015
    }
    
  6. Hans-Georg König, Karen S Coughlan, Sinéad Kinsella, Bridget A Breen and Jochen H M Prehn.
    The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes.. Neurobiology of disease 70:99–107, 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-$\kappa$B in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non-cell autonomous motoneuron degeneration in ALS.
    URL, DOI BibTeX

    @article{Konig2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-$\kappa$B in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non-cell autonomous motoneuron degeneration in ALS.",
    	author = {K\"{o}nig, Hans-Georg and Coughlan, Karen S and Kinsella, Sin\'{e}ad and Breen, Bridget A and Prehn, Jochen H M},
    	doi = "10.1016/j.nbd.2014.06.008",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	keywords = "Amyotrophic Lateral Sclerosis,Animals,Anterior Horn Cells,Anterior Horn Cells: physiology,Astrocytes,Astrocytes: immunology,BH3 Interacting Domain Death Agonist Protein,BH3 Interacting Domain Death Agonist Protein: anta,BH3 Interacting Domain Death Agonist Protein: gene,BH3 Interacting Domain Death Agonist Protein: meta,Cell Death,Cell Death: physiology,Cells, Cultured,Humans,Lipopolysaccharides,Mice, Knockout,Mice, Transgenic,Microglia,Microglia: immunology,Motor Neurons,Motor Neurons: physiology,NF-kappa B,NF-kappa B: metabolism,Neurodegenerative Diseases,Neurodegenerative Diseases: physiopathology,Neuroimmunomodulation,Neuroimmunomodulation: physiology,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "",
    	pages = "99--107",
    	pmid = 24956542,
    	title = "{The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24956542",
    	volume = 70,
    	year = 2014
    }