Journal
EMBO JOURNAL
Volume 37, Issue 2, Pages 282-299Publisher
WILEY
DOI: 10.15252/embj.201797212
Keywords
disaggregation; HttpolyQ; molecular chaperones; NPCs; suppression
Categories
Funding
- DFG [NeuroCure EXC257, SFB740, SPP1623]
- Daimler Benz Stipend
- AXA Research Fund
- Berlin Institute of Health and Gender Equality Funds
- Bundesministerium fur Bildung und Forschung (e:Bio young investigator grant) [AZ.031A318]
- Berlin Institute of Health [1.1.2.a.3]
- German Federal Ministry for Education and Research (BMBF)
- Helmholtz Validation Fund [HVF-0013]
- Helmholtz Association, Germany
- Medical Research Council [MC_PC_16031] Funding Source: researchfish
- MRC [MC_PC_16031] Funding Source: UKRI
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Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT). Molecular chaperones have been implicated in suppressing or delaying the aggregation of mutant Htt. Using in vitro and in vivo assays, we have identified a trimeric chaperone complex (Hsc70, Hsp110, and J-protein) that completely suppresses fibrilization of HttExon1Q48. The composition of this chaperone complex is variable as recruitment of different chaperone family members forms distinct functional complexes. The trimeric chaperone complex is also able to resolubilize Htt fibrils. We confirmed the biological significance of these findings in HD patient-derived neural cells and on an organismal level in Caenorhabditis elegans. Among the proteins in this chaperone complex, the J-protein is the concentration-limiting factor. The single overexpression of DNAJB1 in HEK293T cells is sufficient to profoundly reduce HttExon1Q97 aggregation and represents a target of future therapeutic avenues for HD.
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