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

被引：622

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

页码：1023 / 1037

页数：15

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