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Henry L Paulson - One of the best experts on this subject based on the ideXlab platform.
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Toward an understanding of Polyglutamine neurodegeneration.
Brain Pathology, 2020Co-Authors: Henry L PaulsonAbstract:Polyglutamine expansion is now recognized to be a major cause of inherited human neurodegenerative disease. The Polyglutamine expansion diseases identified so far are slowly progressive disorders in which distinct yet overlapping brain regions are selectively vulnerable to degeneration. Despite their clinical differences these diseases likely share a common pathogenic mechanism, occurring at the protein level and centered on an abnormal conformation of expanded Polyglutamine in the respective disease proteins. Recently there has been remarkable progress in our understanding of Polyglutamine disease, but still there are many unanswered questions. In this review, I first outline some of the shared features of Polyglutamine diseases and then discuss several issues relevant to an understanding of pathogenesis, paying particular attention to possible mechanisms of neurotoxicity.
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Polyglutamine neurodegeneration protein misfolding revisited
Trends in Neurosciences, 2008Co-Authors: Aislinn J Williams, Henry L PaulsonAbstract:Polyglutamine diseases are a major cause of neurodegeneration worldwide. Recent studies highlight the importance of protein quality control mechanisms in regulating Polyglutamine-induced toxicity. Here we discuss a model of disease pathogenesis that integrates current understanding of the role of protein folding in Polyglutamine disease with emerging evidence that alterations in native protein interactions contribute to toxicity. We also incorporate new findings on other age-related neurodegenerative diseases in an effort to explain how protein aggregation and normal aging processes might be involved in Polyglutamine disease pathogenesis.
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ataxin 3 suppresses Polyglutamine neurodegeneration in drosophila by a ubiquitin associated mechanism
Molecular Cell, 2005Co-Authors: Henry L Paulson, John M Warrick, Nancy M Bonini, Lance Morabito, Julide Bilen, Beth Gordeskygold, Lynn Z FaustAbstract:Summary Two central issues in Polyglutamine-induced neurodegeneration are the influence of the normal function of the disease protein and modulation by protein quality control pathways. By using Drosophila , we now directly link host protein function and disease pathogenesis to ubiquitin pathways in the Polyglutamine disease spinocerebellar ataxia type 3 (SCA3). Normal human ataxin-3—a polyubiquitin binding protein with ubiquitin protease activity—is a striking suppressor of Polyglutamine neurodegeneration in vivo. This suppressor activity requires ubiquitin-associated activities of the protein and is dependent upon proteasome function. Our results highlight the critical importance of host protein function in SCA3 disease and a potential therapeutic role of ataxin-3 activity for Polyglutamine disorders.
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mechanisms of chaperone suppression of Polyglutamine disease selectivity synergy and modulation of protein solubility in drosophila
Human Molecular Genetics, 2000Co-Authors: H Edwin Y Chan, Henry L Paulson, John M Warrick, Gladys L Grayboard, Nancy M BoniniAbstract:At least eight dominant human neurodegenerative diseases are due to the expansion of a Polyglutamine within the disease proteins. This confers toxicity on the proteins and is associated with nuclear inclusion formation. Recent findings indicate that molecular chaperones can modulate Polyglutamine pathogenesis, but the basis of Polyglutamine toxicity and the mechanism by which chaperones suppress neurodegeneration remains unknown. In a Drosophila disease model, we demonstrate that chaperones show substrate specificity for Polyglutamine protein, as well as synergy in suppression of neurotoxicity. Our analysis also reveals that chaperones alter the solubility properties of the protein, indicating that chaperone modulation of neurodegeneration in vivo is associated with altered biochemical properties of the mutant Polyglutamine protein. These findings have implications for these and other human neurodegenerative diseases associated with abnormal protein aggregation.
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creb binding protein sequestration by expanded Polyglutamine
Human Molecular Genetics, 2000Co-Authors: Alexander Mccampbell, Addis A Taye, Paul J Taylor, Jon Robitschek, Mei Li, Jessica Walcott, Diane E Merry, Yaohui Chai, Henry L Paulson, Gen SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded Polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the Polyglutamine expansion. In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by Polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another Polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded Polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from Polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of Polyglutamine expansion disease.
Nobuyuki Nukina - One of the best experts on this subject based on the ideXlab platform.
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E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine
2020Co-Authors: Amit Mishra, Priyanka Dikshit, Sudarshana Purkayastha, Jaiprakash Sharma, Nobuyuki Nukina, Nihar Ranjan JanaAbstract:The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most agerelated neurodegenerative disorders including Polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the Polyglutamine protein aggregation and toxicity. Here we have identified another ubiquitin ligase, called E6-AP, which is able to promote the proteasomal degradation of misfolded Polyglutamine proteins and suppress the Polyglutamine protein aggregation and Polyglutamine protein-induced cell death. E6-AP interacts with the soluble misfolded Polyglutamine protein and associates with their aggregates in both cellular and transgenic mouse models. Partial knockdown of E6-AP enhances the rate of aggregate formation and cell death mediated by the Polyglutamine protein. Finally, we have demonstrated the up-regulation of E6-AP in the expanded Polyglutamine protein-expressing cells as well as cells exposed to proteasomal stress. These findings suggest that E6-AP is a critical mediator of the neuronal response to misfolded Polyglutamine proteins and represents a potential therapeutic target in the Polyglutamine diseases.
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Transcription factor sequestration by Polyglutamine proteins.
Methods of Molecular Biology, 2010Co-Authors: Tomoyuki Yamanaka, Nobuyuki NukinaAbstract:In Polyglutamine diseases including Huntington's disease, the causative gene products containing expanded Polyglutamine form nuclear aggregates in neurons. Recent studies have identified several transcriptional factors, which interact with and are sequestered by expanded Polyglutamine aggregates in neurons. Further, altered expression of many genes has been shown in several Polyglutamine disease models. These observations suggest an involvement of transcriptional dysregulation in pathological process of these diseases. In this chapter, we introduce several methods to examine the interaction of transcriptional factors with and their sequestration by expanded Polyglutamine proteins in vitro and in vivo.
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E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity
Journal of Biological Chemistry, 2008Co-Authors: Amit Mishra, Priyanka Dikshit, Sudarshana Purkayastha, Jaiprakash Sharma, Nobuyuki Nukina, Nihar Ranjan JanaAbstract:Abstract The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age-related neurodegenerative disorders including Polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the Polyglutamine protein aggregation and toxicity. Here we have identified another ubiquitin ligase, called E6-AP, which is able to promote the proteasomal degradation of misfolded Polyglutamine proteins and suppress the Polyglutamine protein aggregation and Polyglutamine protein-induced cell death. E6-AP interacts with the soluble misfolded Polyglutamine protein and associates with their aggregates in both cellular and transgenic mouse models. Partial knockdown of E6-AP enhances the rate of aggregate formation and cell death mediated by the Polyglutamine protein. Finally, we have demonstrated the up-regulation of E6-AP in the expanded Polyglutamine protein-expressing cells as well as cells exposed to proteasomal stress. These findings suggest that E6-AP is a critical mediator of the neuronal response to misfolded Polyglutamine proteins and represents a potential therapeutic target in the Polyglutamine diseases.
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co chaperone chip associates with expanded Polyglutamine protein and promotes their degradation by proteasomes
Journal of Biological Chemistry, 2005Co-Authors: Nihar Ranjan Jana, Priyanka Dikshit, Anand Goswami, Svetlana Kotliarova, Shigeo Murata, Keiji Tanaka, Nobuyuki NukinaAbstract:Abstract A major hallmark of the Polyglutamine diseases is the formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various chaperones and proteasome components. But, how the Polyglutamine proteins are ubiquitinated and degraded by the proteasomes are not known. Here, we demonstrate that CHIP (C terminus of Hsp70-interacting protein) co-immunoprecipitates with the Polyglutamine-expanded huntingtin or ataxin-3 and associates with their aggregates. Transient overexpression of CHIP increases the ubiquitination and the rate of degradation of Polyglutamine-expanded huntingtin or ataxin-3. Finally, we show that overexpression of CHIP suppresses the aggregation and cell death mediated by expanded Polyglutamine proteins and the suppressive effect is more prominent when CHIP is overexpressed along with Hsc70.
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BAG-1 associates with the Polyglutamine-expanded huntingtin aggregates
Neuroscience Letters, 2005Co-Authors: Nihar Ranjan Jana, Nobuyuki NukinaAbstract:Abstract Huntington's disease (HD) is characterised by the proteolytic production of N-terminal fragments of huntingtin containing Polyglutamine repeats that forms intracellular ubiquitinated aggregates in the affected neurons. Using cellular and transgenic mice model of HD, we report here that BAG-1 co-immunoprecipitates with the Polyglutamine-expanded truncated N-terminal huntingtin (tNhtt) and associates with their aggregates through its interaction with the chaperones Hsc70/Hsp70. We further demonstrate that the over expression of BAG-1 protects Polyglutamine-expanded tNhtt induced cell death. Since, BAG-1 is essential for cell survival, its association with tNhtt aggregates might disrupt its normal function and thereby promote Polyglutamine-expanded tNhtt-induced cell death.
Nihar Ranjan Jana - One of the best experts on this subject based on the ideXlab platform.
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E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine
2020Co-Authors: Amit Mishra, Priyanka Dikshit, Sudarshana Purkayastha, Jaiprakash Sharma, Nobuyuki Nukina, Nihar Ranjan JanaAbstract:The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most agerelated neurodegenerative disorders including Polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the Polyglutamine protein aggregation and toxicity. Here we have identified another ubiquitin ligase, called E6-AP, which is able to promote the proteasomal degradation of misfolded Polyglutamine proteins and suppress the Polyglutamine protein aggregation and Polyglutamine protein-induced cell death. E6-AP interacts with the soluble misfolded Polyglutamine protein and associates with their aggregates in both cellular and transgenic mouse models. Partial knockdown of E6-AP enhances the rate of aggregate formation and cell death mediated by the Polyglutamine protein. Finally, we have demonstrated the up-regulation of E6-AP in the expanded Polyglutamine protein-expressing cells as well as cells exposed to proteasomal stress. These findings suggest that E6-AP is a critical mediator of the neuronal response to misfolded Polyglutamine proteins and represents a potential therapeutic target in the Polyglutamine diseases.
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E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity
Journal of Biological Chemistry, 2008Co-Authors: Amit Mishra, Priyanka Dikshit, Sudarshana Purkayastha, Jaiprakash Sharma, Nobuyuki Nukina, Nihar Ranjan JanaAbstract:Abstract The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age-related neurodegenerative disorders including Polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the Polyglutamine protein aggregation and toxicity. Here we have identified another ubiquitin ligase, called E6-AP, which is able to promote the proteasomal degradation of misfolded Polyglutamine proteins and suppress the Polyglutamine protein aggregation and Polyglutamine protein-induced cell death. E6-AP interacts with the soluble misfolded Polyglutamine protein and associates with their aggregates in both cellular and transgenic mouse models. Partial knockdown of E6-AP enhances the rate of aggregate formation and cell death mediated by the Polyglutamine protein. Finally, we have demonstrated the up-regulation of E6-AP in the expanded Polyglutamine protein-expressing cells as well as cells exposed to proteasomal stress. These findings suggest that E6-AP is a critical mediator of the neuronal response to misfolded Polyglutamine proteins and represents a potential therapeutic target in the Polyglutamine diseases.
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co chaperone chip associates with expanded Polyglutamine protein and promotes their degradation by proteasomes
Journal of Biological Chemistry, 2005Co-Authors: Nihar Ranjan Jana, Priyanka Dikshit, Anand Goswami, Svetlana Kotliarova, Shigeo Murata, Keiji Tanaka, Nobuyuki NukinaAbstract:Abstract A major hallmark of the Polyglutamine diseases is the formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various chaperones and proteasome components. But, how the Polyglutamine proteins are ubiquitinated and degraded by the proteasomes are not known. Here, we demonstrate that CHIP (C terminus of Hsp70-interacting protein) co-immunoprecipitates with the Polyglutamine-expanded huntingtin or ataxin-3 and associates with their aggregates. Transient overexpression of CHIP increases the ubiquitination and the rate of degradation of Polyglutamine-expanded huntingtin or ataxin-3. Finally, we show that overexpression of CHIP suppresses the aggregation and cell death mediated by expanded Polyglutamine proteins and the suppressive effect is more prominent when CHIP is overexpressed along with Hsc70.
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BAG-1 associates with the Polyglutamine-expanded huntingtin aggregates
Neuroscience Letters, 2005Co-Authors: Nihar Ranjan Jana, Nobuyuki NukinaAbstract:Abstract Huntington's disease (HD) is characterised by the proteolytic production of N-terminal fragments of huntingtin containing Polyglutamine repeats that forms intracellular ubiquitinated aggregates in the affected neurons. Using cellular and transgenic mice model of HD, we report here that BAG-1 co-immunoprecipitates with the Polyglutamine-expanded truncated N-terminal huntingtin (tNhtt) and associates with their aggregates through its interaction with the chaperones Hsc70/Hsp70. We further demonstrate that the over expression of BAG-1 protects Polyglutamine-expanded tNhtt induced cell death. Since, BAG-1 is essential for cell survival, its association with tNhtt aggregates might disrupt its normal function and thereby promote Polyglutamine-expanded tNhtt-induced cell death.
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increased expression of p62 in expanded Polyglutamine expressing cells and its association with Polyglutamine inclusions
Journal of Neurochemistry, 2004Co-Authors: Utako Nagaoka, Nihar Ranjan Jana, Mieko Maruyama, Kenichi Mitsui, Fumitaka Oyama, Nobuyuki NukinaAbstract:Huntington's disease is a progressive neurodegenerative disorder that is associated with a CAG repeat expansion in the gene encoding huntingtin. We found that a 60-kDa protein was increased in Neuro2a cells expressing the N-terminal portion of huntingtin with expanded Polyglutamine. We purified this protein, and, using mass spectrometry, identified it as p62, an ubiquitin-associated domain-containing protein. A specific p62 antibody stained the ubiquitylated polyQ inclusions in expanded Polyglutamine-expressing cells, as well as in the brain of the huntingtin exon 1 transgenic mice. Furthermore, the level of p62 protein and mRNA was increased in expanded Polyglutamine-expressing cells. We also found that p62 formed aggresome-like inclusions when p62 was increased in normal Neuro2a cells by a proteasome inhibitor. Knock-down of p62 does not affect the formation of aggresomes or Polyglutamine inclusions, suggesting that p62 is recruited to the aggresome or inclusions secondary to their formation. These results suggest that p62 may play important roles as a responsive protein to a Polyglutamine-induced stress rather than as a cross-linker between ubiquitylated proteins.
James R. Burke - One of the best experts on this subject based on the ideXlab platform.
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Phage Display Screening for Peptides that Inhibit Polyglutamine Aggregation
Methods in Enzymology, 2020Co-Authors: Daniel J. Kenan, Warren J. Strittmatter, James R. BurkeAbstract:Abstract Proteins with expanded Polyglutamine domains cause nine dominantly inherited, neurodegenerative diseases, including Huntington's disease. There are no therapies that inhibit disease onset or progression. To identify a novel therapeutic, we screened phage displayed peptide libraries for phage that bind preferentially to expanded Polyglutamine repeats. We identified a peptide motif that inhibits Polyglutamine aggregation in vitro and inhibits death in cellular and Drosophila models of the Polyglutamine repeat diseases. In this chapter, we describe in detail how to screen a peptide phage display library and highlight results demonstrating the success of this approach. A similar experimental approach could be used for other diseases caused by conformational change in disease proteins, including prion, Alzheimer's, and Parkinson's diseases.
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Phage Display Screening for Peptides that Inhibit Polyglutamine Aggregation
Methods in Enzymology, 2006Co-Authors: Daniel J. Kenan, Warren J. Strittmatter, James R. BurkeAbstract:Proteins with expanded Polyglutamine domains cause nine dominantly inherited, neurodegenerative diseases, including Huntington's disease. There are no therapies that inhibit disease onset or progression. To identify a novel therapeutic, we screened phage displayed peptide libraries for phage that bind preferentially to expanded Polyglutamine repeats. We identified a peptide motif that inhibits Polyglutamine aggregation in vitro and inhibits death in cellular and Drosophila models of the Polyglutamine repeat diseases. In this chapter, we describe in detail how to screen a peptide phage display library and highlight results demonstrating the success of this approach. A similar experimental approach could be used for other diseases caused by conformational change in disease proteins, including prion, Alzheimer's, and Parkinson's diseases. © 2006 Elsevier Inc. All rights reserved.
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Inhibition of Polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening
Journal of Biological Chemistry, 2000Co-Authors: Yoshitaka Nagai, Warren J. Strittmatter, Timothy Tucker, Hongzu Ren, Barry S. Henderson, Daniel J. Kenan, Jack D Keene, James R. BurkeAbstract:Proteins with expanded Polyglutamine domains cause eight inherited neurodegenerative diseases, including Huntington's, but the molecular mechanism(s) responsible for neuronal degeneration are not yet established. Expanded Polyglutamine domain proteins possess properties that distinguish them from the same proteins with shorter glutamine repeats. Unlike proteins with short Polyglutamine domains, proteins with expanded Polyglutamine domains display unique protein interactions, form intracellular aggregates, and adopt a novel conformation that can be recognized by monoclonal antibodies. Any of these Polyglutamine length-dependent properties could be responsible for the pathogenic effects of expanded Polyglutamine proteins. To identify peptides that interfere with pathogenic Polyglutamine interactions, we screened a combinatorial peptide library expressed on M13 phage pIII protein to identify peptides that preferentially bind pathologic-length Polyglutamine domains. We identified six tryptophan-rich peptides that preferentially bind pathologic-length Polyglutamine domain proteins. Polyglutamine-binding peptide 1 (QBP1) potently inhibits Polyglutamine protein aggregation in an in vitro assay, while a scrambled sequence has no effect on aggregation. QBP1 and a tandem repeat of QBP1 also inhibit aggregation of Polyglutamine-yellow fluorescent fusion protein in transfected COS-7 cells. Expression of QBP1 potently inhibits Polyglutamine-induced cell death. Selective inhibition of pathologic interactions of expanded Polyglutamine domains with themselves or other proteins may be a useful strategy for preventing disease onset or for slowing progression of the Polyglutamine repeat diseases.
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Expanded Polyglutamine Domain Proteins Bind Neurofilament and Alter the Neurofilament Network
Experimental Neurology, 1999Co-Authors: Yoshitaka Nagai, Warren J. Strittmatter, Osamu Onodera, Jerold Chun, James R. BurkeAbstract:Eight inherited neurodegenerative diseases are caused by genes with expanded CAG repeats coding for Polyglutamine domains in the disease-producing proteins. The mechanism by which this expanded Polyglutamine domain causes neurodegenerative disease is unknown, but nuclear and cytoplasmic Polyglutamine protein aggregation is a common feature. In transfected COS7 cells, expanded Polyglutamine proteins aggregate and disrupt the vimentin intermediate filament network. Since neurons have an intermediate filament network composed of neurofilament (NF) and NF abnormalities occur in neurodegenerative diseases, we examined whether pathologic-length Polyglutamine domain proteins also interact with NF. We expressed varying lengths Polyglutamine-green fluorescent protein fusion proteins in a neuroblast cell line, TR1. Pathologic-length Polyglutamine-GFP fusion proteins formed large cytoplasmic aggregates surrounded by neurofilament. Immunoisolation of pathologic-length Polyglutamine proteins coisolated 68-kDa NF protein demonstrating molecular interaction. These observations suggest that Polyglutamine interaction with NF is important in the pathogenesis of the Polyglutamine repeat diseases.
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Toxicity of expanded Polyglutamine‐domain proteins in Escherichia coli
FEBS Letters, 1996Co-Authors: Osamu Onodera, Warren J. Strittmatter, Shoji Tsuji, J M Vance, Allen D. Rose, James R. BurkeAbstract:Five neurodegenerative diseases are caused by proteins with expanded Polyglutamine domains. Toxicity of these proteins has been previously identified only in mammals, and no simple model systems are available. In this paper, we demonstrate in E. coli that long Polyglutamine domains (59–81 residues) as GST-fusion proteins inhibit growth while smaller glutamine (10–35 residues) or polyalanine (61 residues) domains have no effect. Analogously in humans, Polyglutamine repeats less than 35–40 glutamines produce a normal phenotype, while expansion greater than 40 glutamines is always associated with disease. Expression of Polyglutamine proteins in E. coli may help identify the molecular mechanism of pathogenesis of CAG trinucleotide repeat diseases and be a useful screen to identify potential therapeutic compounds.
Nancy M Bonini - One of the best experts on this subject based on the ideXlab platform.
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Hosting Neurotoxicity in Polyglutamine Disease
Cell, 2006Co-Authors: Nancy M BoniniAbstract:Polyglutamine diseases are caused by an expanded glutamine domain thought to confer a toxic activity onto the respective disease proteins. In this issue, Lam et al. (2006) propose that toxicity of the Polyglutamine protein Ataxin-1 may not be due to abberant protein interactions mediated by the Polyglutamine expansion. Instead, they suggest that toxicity is solely due to interactions of Ataxin-1 with its normal binding partners.
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ataxin 3 suppresses Polyglutamine neurodegeneration in drosophila by a ubiquitin associated mechanism
Molecular Cell, 2005Co-Authors: Henry L Paulson, John M Warrick, Nancy M Bonini, Lance Morabito, Julide Bilen, Beth Gordeskygold, Lynn Z FaustAbstract:Summary Two central issues in Polyglutamine-induced neurodegeneration are the influence of the normal function of the disease protein and modulation by protein quality control pathways. By using Drosophila , we now directly link host protein function and disease pathogenesis to ubiquitin pathways in the Polyglutamine disease spinocerebellar ataxia type 3 (SCA3). Normal human ataxin-3—a polyubiquitin binding protein with ubiquitin protease activity—is a striking suppressor of Polyglutamine neurodegeneration in vivo. This suppressor activity requires ubiquitin-associated activities of the protein and is dependent upon proteasome function. Our results highlight the critical importance of host protein function in SCA3 disease and a potential therapeutic role of ataxin-3 activity for Polyglutamine disorders.
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mechanisms of chaperone suppression of Polyglutamine disease selectivity synergy and modulation of protein solubility in drosophila
Human Molecular Genetics, 2000Co-Authors: H Edwin Y Chan, Henry L Paulson, John M Warrick, Gladys L Grayboard, Nancy M BoniniAbstract:At least eight dominant human neurodegenerative diseases are due to the expansion of a Polyglutamine within the disease proteins. This confers toxicity on the proteins and is associated with nuclear inclusion formation. Recent findings indicate that molecular chaperones can modulate Polyglutamine pathogenesis, but the basis of Polyglutamine toxicity and the mechanism by which chaperones suppress neurodegeneration remains unknown. In a Drosophila disease model, we demonstrate that chaperones show substrate specificity for Polyglutamine protein, as well as synergy in suppression of neurotoxicity. Our analysis also reveals that chaperones alter the solubility properties of the protein, indicating that chaperone modulation of neurodegeneration in vivo is associated with altered biochemical properties of the mutant Polyglutamine protein. These findings have implications for these and other human neurodegenerative diseases associated with abnormal protein aggregation.
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suppression of Polyglutamine mediated neurodegeneration in drosophila by the molecular chaperone hsp70
Nature Genetics, 1999Co-Authors: John M Warrick, Yaohui Chai, Henry L Paulson, H Edwin Y Chan, Gladys L Grayboard, Nancy M BoniniAbstract:At least eight inherited human neurodegenerative diseases are caused by expansion of a Polyglutamine domain within the respective proteins1,2. This confers dominant toxicity on the proteins, leading to dysfunction and loss of neurons. Expanded Polyglutamine proteins form aggregates, including nuclear inclusions (NI), within neurons, possibly due to misfolding of the proteins3,4,5. NI are ubiquitinated and sequester molecular chaperone proteins and proteasome components6,7,8,9, suggesting that disease pathogenesis includes activation of cellular stress pathways to help refold, disaggregate or degrade the mutant disease proteins. Overexpression of specific chaperone proteins reduces Polyglutamine aggregation in transfected cells7,8,9, but whether this alters toxicity is unknown. Using a Drosophila melanogaster model of Polyglutamine disease10, we show that directed expression of the molecular chaperone HSP70 suppresses Polyglutamine-induced neurodegeneration in vivo. Suppression by HSP70 occurred without a visible effect on NI formation, indicating that Polyglutamine toxicity can be dissociated from formation of large aggregates. Our studies indicate that HSP70 or related molecular chaperones may provide a means of treating these and other neurodegenerative diseases associated with abnormal protein conformation and toxicity.
