MPP+ impairs autophagic clearance of alpha-synuclein by impairing the activity of dynein.
Increasing evidence suggests that dynein has an important role in the clearance of misfolded proteins by autophagy. Here we show that treatment of cells with 1-methyl-4-phenylpyridinium (MPP) cause alpha-synuclein overexpression and aggregation, leading to the accumulation of autophagic vacuoles and the recruitment of LC3-II to these vacuoles in the cytoplasm. After MPP treatment, dynein expression decreased and was mainly aggregated at the periphery of cytoplasm and lost its colocalization with alpha-synuclein and lamp1, indicating that dynein lost its function in the aggresome formation and failed to return autophagosome and lysosomes to the center of the cell for degradation. We consider that dynein plays an important role in the autophagic clearance of aggregate-prone proteins.
Cai
Zeng-Lin
ZL
Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, China.
Shi
Ji-Jun
JJ
Yang
Ya-Ping
YP
Cao
Bi-Yin
BY
Wang
Feng
F
Huang
Jin-Zhong
JZ
Yang
Fang
F
Zhang
Ping
P
Liu
Chun-Feng
CF
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002374:Catalase / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
D015655:1-Methyl-4-phenylpyridinium; D002374:Catalase; D004398:Dyneins; D004791:Enzyme Inhibitors; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D019311:Staurosporine; D013482:Superoxide Dismutase; D051844:alpha-Synuclein; C526109:Anxa3 protein, rat; C489117:Lamp1 protein, rat; D052118:Lysosomal-Associated Membrane Protein 1