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Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
Suzhou Key Laboratory of Translational Research of Neuro-Psycho-Diseases and Department of Neurology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China
Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou 215123, China
* Authors to whom correspondence should be addressed.
Received: 11 September 2013; in revised form: 26 November 2013 / Accepted: 3 December 2013 / Published: 13 December 2013
Abstract: Growing evidence suggests that dynein dysfunction may be implicated in the pathogenesis of neurodegeneration. It plays a central role in aggresome formation, the delivery of autophagosome to lysosome for fusion and degradation, which is a pro-survival mechanism essential for the bulk degradation of misfolded proteins and damaged organells. Previous studies reported that dynein dysfuntion was associated with aberrant aggregation of α-synuclein, which is a major component of inclusion bodies in Parkinson’s disease (PD). However, it remains unclear what roles dynein plays in α-synuclein degradation. Our study demonstrated a decrease of dynein expression in neurotoxin-induced PD models in vitro and in vivo, accompanied by an increase of α-synuclein protein level. Dynein down-regulation induced by siRNA resulted in a prolonged half-life of α-synuclein and its over-accumulation in A53T overexpressing PC12 cells. Dynein knockdown also prompted the increase of microtubule-associated protein 1 light chain 3 (LC3-II) and sequestosome 1 (SQSTM1, p62) expression, and the accumulation of autophagic vacuoles. Moreover, dynein suppression impaired the autophagosome fusion with lysosome. In summary, our findings indicate that dynein is critical for the clearance of aberrant α-synuclein via autophagosome-lysosome pathway.
Keywords: dynein; α-synuclein; Parkinson’s disease; autophagy; autolysosome
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Li, D.; Shi, J.-J.; Mao, C.-J.; Liu, S.; Wang, J.-D.; Chen, J.; Wang, F.; Yang, Y.-P.; Hu, W.-D.; Hu, L.-F.; Liu, C.-F. Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway. Int. J. Mol. Sci. 2013, 14, 24242-24254.
Li D, Shi J-J, Mao C-J, Liu S, Wang J-D, Chen J, Wang F, Yang Y-P, Hu W-D, Hu L-F, Liu C-F. Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway. International Journal of Molecular Sciences. 2013; 14(12):24242-24254.
Li, Da; Shi, Ji-Jun; Mao, Cheng-Jie; Liu, Sha; Wang, Jian-Da; Chen, Jing; Wang, Fen; Yang, Ya-Ping; Hu, Wei-Dong; Hu, Li-Fang; Liu, Chun-Feng. 2013. "Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway." Int. J. Mol. Sci. 14, no. 12: 24242-24254.