Document Type
Article
Publication Date
12-2010
Publisher
The American Society for Biochemistry and Molecular Biology
Source Publication
Journal of Biological Chemistry
Source ISSN
0021-9258
Abstract
Inclusion bodies of aggregated mutant huntingtin (htt) fragments are a neuropathological hallmark of Huntington disease (HD). The molecular chaperones Hsp70 and Hsp40 colocalize to inclusion bodies and are neuroprotective in HD animal models. How these chaperones suppress mutant htt toxicity is unclear but might involve direct effects on mutant htt misfolding and aggregation. Using size exclusion chromatography and atomic force microscopy, we found that mutant htt fragments assemble into soluble oligomeric species with a broad size distribution, some of which reacted with the conformation-specific antibody A11. Hsp70 associated with A11-reactive oligomers in an Hsp40- and ATP-dependent manner and inhibited their formation coincident with suppression of caspase 3 activity in PC12 cells. Thus, Hsp70 and Hsp40 (DNAJB1) dynamically target specific subsets of soluble oligomers in a classic ATP-dependent reaction cycle, supporting a pathogenic role for these structures in HD.
Recommended Citation
Lotz, Gregor P.; Legleiter, Justin; Aron, Rebecca; Sontag, Emily M.; Huang, Shao-Yi; Ng, Cheping; Glabe, Charles G.; Thompson, Leslie M.; and Muchowski, Paul J., "Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-Dependent Reaction Cycle" (2010). Biological Sciences Faculty Research and Publications. 902.
https://epublications.marquette.edu/bio_fac/902
Comments
Published version. Journal of Biological Chemistry, Vol. 285, No. 49 (December 2010): 38193-38193. DOI. © 2010 The American Society for Biochemistry and Molecular Biology. Used with permission.
Emily J. Mitchell (Sontag) was affiliated with the University of California, Irvine at the time of publication.