α-Synuclein impairs macroautophagy: implications for Parkinson's disease

被引：592
|
作者：
Winslow, Ashley R. [1 ]
Chen, Chien-Wen [1 ,3 ]
Corrochano, Silvia [4 ]
Acevedo-Arozena, Abraham [4 ]
Gordon, David E. [2 ]
Peden, Andrew A. [2 ]
Lichtenberg, Maike [1 ]
Menzies, Fiona M. [1 ]
Ravikumar, Brinda [1 ]
Imarisio, Sara [1 ,3 ]
Brown, Steve [4 ]
O'Kane, Cahir J. [3 ]
Rubinsztein, David C. [1 ]
机构：
[1] Univ Cambridge, Dept Med Genet, Cambridge CB2 OXY, England
[2] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 OXY, England
[3] Univ Cambridge, Dept Genet, Cambridge CB2 OXY, England
[4] MRC, Mammalian Genet Unit, Harwell OX11 0RD, Oxon, England
来源：
JOURNAL OF CELL BIOLOGY | 2010年 / 190卷 / 06期
基金：
英国医学研究理事会; 英国惠康基金;
关键词：
CHAPERONE-MEDIATED AUTOPHAGY; AGGREGATE-PRONE PROTEINS; MUTANT HUNTINGTIN; UNCONVENTIONAL SECRETION; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; PROTEASOMAL FUNCTION; VESICLE FORMATION; DROSOPHILA; POLYGLUTAMINE;
D O I：
10.1083/jcb.201003122
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Parkinson's disease (PD) is characterized pathologically by intraneuronal inclusions called Lewy bodies, largely comprised of alpha-synuclein. Multiplication of the alpha-synuclein gene locus increases alpha-synuclein expression and causes PD. Thus, overexpression of wildtype alpha-synuclein is toxic. In this study, we demonstrate that alpha-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Our data show that alpha-synuclein compromises autophagy via Rab1a inhibition and Rab1a overexpression rescues the autophagy defect caused by alpha-synuclein. Inhibition of autophagy by alpha-synuclein overexpression or Rab1a knockdown causes mislocalization of the autophagy protein, Atg9, and decreases omegasome formation. Rab1a, alpha-synuclein, and Atg9 all regulate formation of the omegasome, which marks autophagosome precursors.
引用
收藏
页码：1023 / 1037
页数：15
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