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

• Published in: The EMBO journal 2018-01, Vol.37 (2), p.282-299
• Main Authors: Scior, Annika, Buntru, Alexander, Arnsburg, Kristin, Ast, Anne, Iburg, Manuel, Juenemann, Katrin, Pigazzini, Maria Lucia, Mlody, Barbara, Puchkov, Dmytro, Priller, Josef, Wanker, Erich E, Prigione, Alessandro, Kirstein, Janine
• Format: Article
• Language: English
• Subjects: Agglomeration; Animals; Caenorhabditis elegans; Chaperones; Disaggregation; EMBO24; EMBO27; EMBO32; Fibrillogenesis; Fibrils; HEK293 Cells; HSC70 Heat-Shock Proteins - chemistry; HSC70 Heat-Shock Proteins - genetics; HSC70 Heat-Shock Proteins - metabolism; Hsc70 protein; HSP110 Heat-Shock Proteins - chemistry; HSP110 Heat-Shock Proteins - genetics; HSP110 Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins - chemistry; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; HttpolyQ; Humans; Huntingtin; Huntingtin Protein - chemistry; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Mammalian cells; molecular chaperones; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; NPCs; Polyglutamine; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Proteins; suppression; Trinucleotide repeats
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201797212

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. Synopsis A dynamic chaperone complex of Hsc70, Hsp110 and J‐protein dissolves pathological Huntingtin fibrils in vitro and prevents aggregate formation in Huntington's disease patient‐derived neurons. Hsc70, a type B J‐protein and Hsp110 fully supress fibrilization of huntingtin exon1 for at least 24 h in vitro . The same chaperones can disaggregate preformed Huntingtin (Htt) fibrils. Depletion of these chaperones enhances Htt aggregation in C. elegans and HD patient‐derived neural cells. Overexpression of DNAJB1 reduces Htt fibril formation in mammalian cells. Graphical Abstract A dynamic chaperone complex of Hsc70, Hsp110 and J‐protein dissolves pathological Huntingtin fibrils in vitro and prevents aggregate formation in Huntington's disease patient‐derived neurons.