α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation.
Proc Natl Acad Sci U S A
; 114(5): 1183-1188, 2017 01 31.
Article
in En
| MEDLINE
| ID: mdl-28096359
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Adenylate Kinase
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Lewy Bodies
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GTP-Binding Proteins
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GTPase-Activating Proteins
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Alpha-Synuclein
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Dopaminergic Neurons
Limits:
Aged
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Aged80
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Animals
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Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2017
Type:
Article