Conformational diseases are neurodegenerative maladies in which the accumulation of amyloid-like fibrillar forms of aberrantly folded proteins cause dementia and cell death via unknown mechanisms. Hsp40s are molecular chaperones that direct Hsp70 to interact with disease related proteins and partition them between pathways for folding, aggregation and amyloid formation. Prions are infectious proteins that that assemble into a self-perpetuating amyloid-like state that is associated with neurodegeneration. The study of yeast prions has provided many of the basic details about chaperone function in amyloid fibril formation. In preliminary studies we developed a number of assays to monitor Hsp40 action in modulating amyloid formation and toxicity. The studies proposed herein are designed to define mechanisms by which aberrant prion biogenesis causes cell death. In addition, we seek to identify the specific steps in prion assembly that are catalyzed by different Hsp40s. Finally, we will determine the structure and functional features of Type I and II Hsp40 sub-types that specify their action in prion biogenesis. The data obtained from these studies will define the rules for Hsp40 function in amyloid formation and identify therapeutic targets for the treatment of conformational disease. Conformational diseases are a neurodegenerative maladies in which the accumulation of amyloid-like fibrillar forms of aberrantly folded proteins cause deimentia and cell death via unknown mechanisms. The data obtained from the proposed studies will define the rules for Hsp40 function in modulation of amyloid formation and toxicity and identify therapeutic targets for the treatment of conformational disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067785-07
Application #
7740178
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wehrle, Janna P
Project Start
2003-05-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
7
Fiscal Year
2010
Total Cost
$285,897
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Veit, Gudio; Avramescu, Radu G; Chiang, Annette N et al. (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424-33
Vermulst, Marc; Denney, Ashley S; Lang, Michael J et al. (2015) Transcription errors induce proteotoxic stress and shorten cellular lifespan. Nat Commun 6:8065
Wolfe, Katie J; Ren, Hong Yu; Trepte, Philipp et al. (2014) Polyglutamine-rich suppressors of huntingtin toxicity act upstream of Hsp70 and Sti1 in spatial quality control of amyloid-like proteins. PLoS One 9:e95914
Houck, Scott A; Ren, Hong Yu; Madden, Victoria J et al. (2014) Quality control autophagy degrades soluble ERAD-resistant conformers of the misfolded membrane protein GnRHR. Mol Cell 54:166-179
Ren, Hong Yu; Grove, Diane E; De La Rosa, Oxana et al. (2013) VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 24:3016-24
Wolfe, Katie J; Ren, Hong Yu; Trepte, Philipp et al. (2013) The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins. Mol Biol Cell 24:3588-602
Borges, JĂșlio C; Seraphim, Thiago V; Mokry, David Z et al. (2012) Identification of regions involved in substrate binding and dimer stabilization within the central domains of yeast Hsp40 Sis1. PLoS One 7:e50927
Wolfe, Katie J; Cyr, Douglas M (2011) Amyloid in neurodegenerative diseases: friend or foe? Semin Cell Dev Biol 22:476-81
Ren, Hong Yu; Patterson, Cam; Cyr, Douglas M et al. (2011) Reconstitution of CHIP E3 ubiquitin ligase activity. Methods Mol Biol 787:93-103
Silva, Julio C; Borges, Julio C; Cyr, Douglas M et al. (2011) Central domain deletions affect the SAXS solution structure and function of yeast Hsp40 proteins Sis1 and Ydj1. BMC Struct Biol 11:40

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