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

Autor: Scior A; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany., Buntru A; Max Delbrueck Center for Molecular Medicine, Berlin, Germany., Arnsburg K; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany., Ast A; Max Delbrueck Center for Molecular Medicine, Berlin, Germany., Iburg M; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany., Juenemann K; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany., Pigazzini ML; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany.; Charité - Universitätsmedizin and NeuroCure Cluster of Excellence, Berlin, Germany., Mlody B; Max Delbrueck Center for Molecular Medicine, Berlin, Germany., Puchkov D; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany., Priller J; Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charite Universitätsmedizin Berlin, Berlin, Germany., Wanker EE; Max Delbrueck Center for Molecular Medicine, Berlin, Germany ewanker@mdc-berlin.de kirstein@fmp-berlin.de., Prigione A; Max Delbrueck Center for Molecular Medicine, Berlin, Germany., Kirstein J; Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany ewanker@mdc-berlin.de kirstein@fmp-berlin.de.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2018 Jan 17; Vol. 37 (2), pp. 282-299. Date of Electronic Publication: 2017 Dec 06.
DOI: 10.15252/embj.201797212
Abstrakt: 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.
(© 2017 The Authors.)
Databáze: MEDLINE
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