Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex
- 6 December 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 37 (2), 282-299
- https://doi.org/10.15252/embj.201797212
Abstract
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.Keywords
Funding Information
- Daimler und Benz Stiftung
- AXA Research Fund
- Helmholtz-Gemeinschaft
- Deutsche Forschungsgemeinschaft (NeuroCure EXC257, SFB740, SPP!623)
- Bundesministerium für Bildung und Forschung (AZ.031A318, 1.1.2.a.3)
- Helmholtz-Gemeinschaft (HVF‐0013)
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