title: Alteration of dynein function affects α-synuclein degradation via the autophagosome-lysosome pathway.
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.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.forename: Ji-Jun
authors.initials: JJ
authors.lastname: Shi
authors.forename: Cheng-Jie
authors.initials: CJ
authors.lastname: Mao
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.forename: Jian-Da
authors.initials: JD
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Hu
authors.affiliation: 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. hulifang@suda.edu.cn.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Hu
authors.affiliation: 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. liucf@suda.edu.cn.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001343:Autophagy; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016716:PC12 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071456:Sequestosome-1 Protein; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004398:Dyneins; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D051844:alpha-Synuclein; C526109:Anxa3 protein, rat; C491079:Sqstm1 protein, rat