title: Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Gregor P
authors.initials: GP
authors.lastname: Lotz
authors.forename: Justin
authors.initials: J
authors.lastname: Legleiter
authors.forename: Rebecca
authors.initials: R
authors.lastname: Aron
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Mitchell
authors.forename: Shao-Yi
authors.initials: SY
authors.lastname: Huang
authors.forename: Cheping
authors.initials: C
authors.lastname: Ng
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D055503:Protein Multimerization; D051381:Rats; D012995:Solubility
chemical_list: D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000255:Adenosine Triphosphate