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Alpha-synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson’s models

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Abstract

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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Acknowledgements

We thank Drs. Renee Reijo Pera, Theo Palmer, Guangwen Wang (Stanford University Stem Cell Core, supported by California Institute for Regenerative Medicine, GC1R-06673-A to Dr. Michael Snyder), and the National Institute of Neurological Disorders and Stroke (NINDS) human and cell repository (https://stemcells.nindsgenetics.org) for iPSC lines, the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for human postmortem brains, Dr. Leo Pallanck for flies, Dr. Alex Whitworth for antibodies, Dr. Thomas Südhof for constructs, and Ashley E. Gonzalez for technical support. This work was supported by the Michael J. Fox Foundation (X. W.), the Esther A. and Joseph Klingenstein Fund (X. W.), the California Institute of Regenerative Medicine (X. W.), the National Institute of Health (X. W. RO1NS089583), and the Archer Fund (X. W.). The Brain and Body Donation Program is supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation.

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  1. Atossa Shaltouki and Chung-Han Hsieh contributed equally.

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  1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

    Atossa Shaltouki, Chung-Han Hsieh, Min Joo Kim & Xinnan Wang

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  1. Atossa Shaltouki
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AS, CH, and MK designed and performed experiments, and made figures. XW conceived and supervised the project, designed the experiments, and wrote the paper with the assistance from all authors.

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Correspondence to Xinnan Wang.

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Shaltouki, A., Hsieh, CH., Kim, M.J. et al. Alpha-synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson’s models. Acta Neuropathol 136, 607–620 (2018). https://doi.org/10.1007/s00401-018-1873-4

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