The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

被引：116

作者：

Kakkar, Vaishali ^{[1
]}

Mansson, Cecilia ^{[2
]}

de Mattos, Eduardo P. ^{[1
,3
]}

Bergink, Steven ^{[1
]}

van der Zwaag, Marianne ^{[1
]}

van Waarde, Maria A. W. H. ^{[1
]}

Kloosterhuis, Niels J. ^{[4
]}

Melki, Ronald ^{[5
]}

van Cruchten, Remco T. P. ^{[2
]}

Al-Karadaghi, Salam ^{[2
]}

Arosio, Paolo ^{[6
]}

Dobson, Christopher M. ^{[6
]}

Knowles, Tuomas P. J. ^{[6
]}

Bates, Gillian P. ^{[7
]}

van Deursen, Jan M. ^{[8
]}

Linse, Sara ^{[2
]}

van de Sluis, Bart ^{[4
]}

Emanuelsson, Cecilia ^{[2
]}

Kampinga, Harm H. ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, NL-9713 GZ Groningen, Netherlands

[2] Lund Univ, Ctr Mol Prot Sci, Dept Biochem & Struct Biol, S-22100 Lund, Sweden

[3] Univ Fed Rio Grande do Sul, Dept Genet, BR-91501970 Porto Alegre, RS, Brazil

[4] Univ Groningen, Univ Med Ctr Groningen, Mol Genet Sect, Dept Pediat, NL-9713 GZ Groningen, Netherlands

[5] CNRS, Neurosci Paris Saclay Inst Neurosci, F-91190 Gif Sur Yvette, France

[6] Univ Cambridge, Dept Chem, Cambridge CB2 1TN, England

[7] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England

[8] Mayo Clin, Rochester, MN 55905 USA

来源：

MOLECULAR CELL | 2016年 / 62卷 / 02期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 欧洲研究理事会; 瑞典研究理事会;

关键词：

HUNTINGTONS-DISEASE; CO-CHAPERONE; MOLECULAR CHAPERONES; PROTEIN AGGREGATION; MISFOLDED PROTEINS; ANDROGEN RECEPTOR; AMYLOID FORMATION; POLYQ PROTEINS; NEURODEGENERATION; CELLS;

D O I：

10.1016/j.molcel.2016.03.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases.

引用

页码：272 / 283

页数：12

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