The dynamic role of Hsp40 chaperones in protein aggregation and proteotoxicity Public Deposited

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  • March 22, 2019
Creator
  • Douglas, Peter Mahan
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Protein homeostasis or proteostasis involves an intricate balance between the synthesis, folding, localization and degradation of each protein in the cell. Perturbations by age or chronic stress can compromise any one component of this integrated network and initiate a cascade of toxic misfolding events. Protein conformational disorders such as Alzheimer's disease, transmissible spongiform encephalopathies, and the polyglutamine-expansion diseases are characterized by the misfolding and subsequent conversion of disease-related proteins into [beta]-sheet-rich conformers capable of assembling into highly ordered aggregates termed amyloid. For over a century, amyloid fibrils were believed to represent the toxic agent behind these diseases due to their overwhelming presence in postmortem brains of diseased individuals. However, recent evidence has begun to challenge the notion that amyloid formation is the toxic mechanism. Two observations described herein suggest that amyloid formation provides the cell a mechanism to buffer the formation of toxic protein species. First, my studies demonstrate that amyloid formation by the yeast prion protein, Rnq1, protects cells against proteotoxicity. Interestingly, the Hsp40 chaperone, Sis1, mediates the efficient conversion of nascent Rnq1 into amyloid-like, [RNQ+] prion assemblies. Inefficiencies in Sis1-mediated [RNQ+] assembly result in the toxic accumulation of soluble, low molecular weight oligomers. Second, Sis1 activity relocates [RNQ+] prion assembly pathways from the cytosol to the nucleus, in which [RNQ+] assembly was more efficient and less toxic. Sis1 modulates the conformation of [RNQ+] prions which, in turn, act as environmental factors to promote toxicity of a huntingtin's protein exon-1 fragment with an expanded polyglutamine tract (Htt-103Q). Complex formation between [RNQ+] prions and Htt-103Q enabled nuclear [RNQ+] aggregates to attract Htt-103Q from the cytosol to the nucleus, which reduced the efficiency of nuclear Htt-103Q aggregation and exacerbated Htt-103Q toxicity. Thus, amyloid formation appears to represent a protective mechanism to ameliorate the toxic accumulation of small, soluble intermediates in the aggregation pathway. My studies also demonstrate that molecular chaperones directly and indirectly influence the cellular location of amyloidogenic proteins and therefore have a profoundly impact on proteotoxicity because the cytosol and nucleus have different capacities to package disease proteins into benign assemblies.
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  • In Copyright
Advisor
  • Cyr, Douglas
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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