Inhibition of α-synuclein aggregation by small heat shock proteins

被引：103

作者：

Bruinsma, Ilona B. ^{[1
,5
,6
]}

Bruggink, Kim A. ^{[1
,5
,6
]}

Kinast, Karsten ^{[1
,5
,6
]}

Versleijen, Alexandra A. M. ^{[1
]}

Segers-Nolten, Ine M. J. ^{[2
,3
]}

Subramaniam, Vinod ^{[2
,3
]}

Kuiperij, H. Bea ^{[1
,5
,6
]}

Boelens, Wilbert ^{[7
,8
]}

de Waal, Robert M. W. ^{[4
]}

Verbeek, Marcel M. ^{[1
,5
,6
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Lab Med,Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands

[2] Univ Twente, Mesa Inst Nanotechnol, NL-7500 AE Enschede, Netherlands

[3] Univ Twente, MIRA Inst Biomed Engn & Tech Med, NL-7500 AE Enschede, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Pathol,Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Donders Inst Brain Cognit & Behav,Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Alzheimer Ctr, Donders Inst Brain Cognit & Behav,Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Dept Biomol Chem, Donders Inst Brain Cognit & Behav,Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands

[8] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Donders Inst Brain Cognit & Behav,Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands

来源：

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS | 2011年 / 79卷 / 10期

关键词：

alpha-synuclein; small heat shock proteins; aggregation; fibrillization; alpha-synucleinopathy; AMYLOID FIBRIL FORMATION; B-CRYSTALLIN; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; CHAPERONE; MUTATION; HSPB8; PATHOGENESIS; OLIGOMERS; MUTANTS;

D O I：

10.1002/prot.23152

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The fibrillization of alpha-synuclein (alpha-syn) is a key event in the pathogenesis of alpha-synucleinopathies. Mutant alpha-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides alpha-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since alpha-syn accumulates intracellularly, molecular chaperones like sHsps may regulate alpha-syn folding and aggregation. Therefore, we investigated if the sHsps alpha B-crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to alpha-syn and affect alpha-syn aggregation. We demonstrate that all sHsps bind to the various alpha-syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature alpha-syn fibril formation as shown by a Thioflavin T assay and atomic force microscopy. Interestingly, HspB8 was the most potent sHsp in inhibiting mature fibril formation of both wild-type and mutant alpha-syn. In conclusion, sHsps may regulate alpha(-)syn aggregation and, therefore, optimization of the interaction between sHsps and alpha-syn may be an interesting target for therapeutic intervention in the pathogenesis of alpha-synucleinopathies.

引用

页码：2956 / 2967

页数：12

共 56 条

[1]

Polydispersity of a mammalian chaperone:: Mass spectrometry reveals the population of oligomers in αB-crystallin [J].