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Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex

Item Type:Article
Title:Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex
Creators Name:Scior, A. and Buntru, A. and Arnsburg, K. and Ast, A. and Iburg, M. and Juenemann, K. and Pigazzini, M.L. and Mlody, B. and Puchkov, D. and Priller, J. and Wanker, E.E. and Prigione, A. and Kirstein, J.
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 HttExon1Q(48) 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 HttExon1Q(97) aggregation and represents a target of future therapeutic avenues for HD.
Keywords:Disaggregation, HttpolyQ, Molecular Chaperones, NPCs, Suppression, Animals
Source:EMBO Journal
ISSN:0261-4189
Publisher:Nature Publishing Group (U.S.A.)
Volume:37
Number:2
Page Range:282-299
Date:17 January 2018
Official Publication:https://doi.org/10.15252/embj.201797212
PubMed:View item in PubMed

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