title: α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation.
abstract: The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP+), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503.
authors.forename: Fredric P
authors.initials: FP
authors.lastname: Manfredsson
authors.affiliation: Department of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Iuvone
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Cao
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Shanghai 200065, China.|Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Department of Neurology, Tongji Hospital, Shanghai 200065, China kye@emory.edu lingjingjin@163.com.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; kye@emory.edu lingjingjin@163.com.|Translational Center for Stem Cell Research, Tongji Hospital, Shanghai 200065, China.|Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000263:Adenylate Kinase / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016923:Cell Death; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000172:deficiency; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency; D010766:Phosphorylation; D000070539:Pleckstrin Homology Domains; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D000263:Adenylate Kinase; C485997:AGAP2 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C529781:PIKE protein, mouse; D015655:1-Methyl-4-phenylpyridinium
keywords: Lewy bodies; dopamine; neurodegenerative disease