Overexpression of human E46K mutant α-synuclein impairs macroautophagy via inactivation of JNK1-Bcl-2 pathway.
Parkinson's disease (PD) is pathologically characterized by selective loss of dopaminergic neurons in the midbrain and the existence of intracellular protein inclusions termed Lewy bodies, largely composed of α-synuclein. Genetic studies have revealed that rare point mutations in the gene encoding α-synuclein including A30P, A53T, and E46K are associated with familial forms of PD, indicating a pathological role for mutant α-synuclein in PD etiology. However, the mechanisms underlying the neuronal toxicity of mutant α-synuclein are still to be elucidated. Growing evidence has suggested a deleterious effect of mutant α-synuclein on the autophagy-lysosome pathway. In this study, we discovered that overexpression of human E46K mutant α-synuclein impaired macroautophagy in mammalian cells. Our data showed that overexpression of E46K mutant α-synuclein impaired autophagy at an early stage of autophagosome formation via the c-Jun N-terminal kinase 1 (JNK1)-Bcl-2 but not the mammalian target of rapamycin (mTOR) pathway. Overexpressed E46K mutant α-synuclein inhibited JNK1 activation, leading to a reduced Bcl-2 phosphorylation and increased association between Bcl-2 and Beclin1, further disrupting the formation of Beclin1/hVps34 complex, which is essential for autophagy initiation. Furthermore, overexpression of E46K mutant α-synuclein increased the vulnerability of differentiated PC12 cells to rotenone treatment, which would be partly due to its inhibitory effects on autophagy. Our findings may shed light on the potential roles of mutant α-synuclein in the pathogenesis of PD.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, I Xiannongtan Street, Xicheng District, 100050, Beijing, People's Republic of China.
Jia-Qing
JQ
Yan
Yu-He
YH
Yuan
Yan-Na
YN
Gao
Ju-Yang
JY
Huang
Kai-Li
KL
Ma
Yan
Y
Gao
Wan-Qing
WQ
Zhang
Xiao-Feng
XF
Guo
Nai-Hong
NH
Chen
D000818:Animals; D001343:Autophagy / Q000502:physiology; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D012402:Rotenone / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*
D019253:Proto-Oncogene Proteins c-bcl-2; C497604:SNCA protein, human; C497606:Snca protein, rat; D051844:alpha-Synuclein; D012402:Rotenone; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048055:Mitogen-Activated Protein Kinase 8