Key result
Hsp70 and Hsp40 inhibit mutant huntingtin oligomer formation and suppress caspase 3 activity in PC12 cells.
Why the study?
The mechanism by which Hsp70 and Hsp40 chaperones suppress mutant huntingtin toxicity by affecting misfolding and aggregation was unclear.
Hsp70 and Hsp40 dynamically target specific subsets of soluble mutant huntingtin oligomers in an ATP-dependent manner, suggesting a mechanism for their neuroprotective effects in Huntington disease.
May guide chaperone-targeted therapies in Huntington disease; hypothesis-generating from cell models and leaves open in vivo translation.
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.
No takes yet. Share an insight, caveat, or question.
Lotz et al. (2010) studied Huntington disease. Hsp70 and Hsp40 was evaluated on Formation of soluble oligomeric species and caspase 3 activity. Hsp70 and Hsp40 dynamically target specific subsets of soluble mutant huntingtin oligomers in an ATP-dependent manner, inhibiting their formation and suppressing caspase 3 activity in PC12 cells.
Synapse has enriched 3 closely related papers on similar clinical questions. Consider them for comparative context: