α-Synuclein impairs macroautophagy: implications for Parkinson's disease.
Parkinson's disease (PD) is characterized pathologically by intraneuronal inclusions called Lewy bodies, largely comprised of α-synuclein. Multiplication of the α-synuclein gene locus increases α-synuclein expression and causes PD. Thus, overexpression of wild-type α-synuclein is toxic. In this study, we demonstrate that α-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Our data show that α-synuclein compromises autophagy via Rab1a inhibition and Rab1a overexpression rescues the autophagy defect caused by α-synuclein. Inhibition of autophagy by α-synuclein overexpression or Rab1a knockdown causes mislocalization of the autophagy protein, Atg9, and decreases omegasome formation. Rab1a, α-synuclein, and Atg9 all regulate formation of the omegasome, which marks autophagosome precursors.
Winslow
Ashley R
AR
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.
Chen
Chien-Wen
CW
Corrochano
Silvia
S
Acevedo-Arozena
Abraham
A
Gordon
David E
DE
Peden
Andrew A
AA
Lichtenberg
Maike
M
Menzies
Fiona M
FM
Ravikumar
Brinda
B
Imarisio
Sara
S
Brown
Steve
S
O'Kane
Cahir J
CJ
Rubinsztein
David C
DC
D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D004331:Drosophila melanogaster / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport; D022142:Secretory Vesicles / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism
C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D051844:alpha-Synuclein; D020761:rab1 GTP-Binding Proteins