α-Synuclein impairs macroautophagy: implications for Parkinson's disease
| Autor: | Chien-Wen Chen, Abraham Acevedo-Arozena, Fiona M. Menzies, David E. Gordon, Cahir J. O'Kane, Steve D.M. Brown, Ashley R. Winslow, Brinda Ravikumar, David C. Rubinsztein, Maike Lichtenberg, Andrew A. Peden, Sara Imarisio, Silvia Corrochano |
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| Rok vydání: | 2010 |
| Předmět: |
Genetically modified mouse
Autophagosome Parkinson's disease animal diseases Golgi Apparatus Biology Models Biological Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Line Tumor Phagosomes mental disorders medicine Autophagy Animals Humans Research Articles 030304 developmental biology Omegasome Alpha-synuclein 0303 health sciences Gene knockdown Secretory Vesicles Membrane Proteins Parkinson Disease Cell Biology medicine.disease nervous system diseases 3. Good health Transport protein Cell biology rab1 GTP-Binding Proteins Protein Transport Drosophila melanogaster nervous system chemistry Gene Knockdown Techniques alpha-Synuclein Microtubule-Associated Proteins 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Cell Biology The Journal of Cell Biology; Vol 190 |
| ISSN: | 1540-8140 |
| Popis: | α-Synuclein impairs autophagosome formation and mislocalizes Atg9 by inhibiting Rab1a. 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. |
| Databáze: | OpenAIRE |
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