期刊
ACTA NEUROPATHOLOGICA
卷 136, 期 4, 页码 607-620出版社
SPRINGER
DOI: 10.1007/s00401-018-1873-4
关键词
Parkinson; Alpha-synuclein; Miro; Mitochondria; Mitophagy; iPSC; Fly; Dopaminergic
资金
- California Institute for Regenerative Medicine [GC1R-06673-A]
- Michael J. Fox Foundation
- Esther A. and Joseph Klingenstein Fund
- California Institute of Regenerative Medicine
- National Institute of Health [RO1NS089583]
- Archer Fund
- NINDS (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Department of Health Services (Arizona Alzheimer's Research Center) [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
Alpha-synuclein is a component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD), and is also mutated in familial PD. Here, by extensively analyzing PD patient brains and neurons, and fly models, we show that alpha-synuclein accumulation results in upregulation of Miro protein levels. Miro is a motor/adaptor on the outer mitochondrial membrane that mediates mitochondrial motility, and is removed from damaged mitochondria to facilitate mitochondrial clearance via mitophagy. PD patient neurons abnormally accumulate Miro on the mitochondrial surface leading to delayed mitophagy. Partial reduction of Miro rescues mitophagy phenotypes and neurodegeneration in human neurons and flies. Upregulation of Miro by alpha-synuclein requires an interaction via the N-terminus of alpha-synuclein. Our results highlight the importance of mitochondria-associated alpha-synuclein in human disease, and present Miro as a novel therapeutic target.
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