@article{d1ca101c422346b78a918292b0659242,
title = "Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models",
abstract = "The identification of molecular targets and pharmacodynamic markers for Parkinson's disease (PD) will empower more effective clinical management and experimental therapies. Miro1 is localized on the mitochondrial surface and mediates mitochondrial motility. Miro1 is removed from depolarized mitochondria to facilitate their clearance via mitophagy. Here, we explore the clinical utility of Miro1 for detecting PD and for gauging potential treatments. We measure the Miro1 response to mitochondrial depolarization using biochemical assays in skin fibroblasts from a broad spectrum of PD patients and discover that more than 94% of the patients{\textquoteright} fibroblast cell lines fail to remove Miro1 following depolarization. We identify a small molecule that can repair this defect of Miro1 in PD fibroblasts. Treating patient-derived neurons and fly models with this compound rescues the locomotor deficits and dopaminergic neurodegeneration. Our results indicate that tracking this Miro1 marker and engaging in Miro1-based therapies could open new avenues to personalized medicine.",
keywords = "Miro1, Parkinson, biomarker, diet, fibroblast, fly, iPSC, mitochondria, mitophagy, neurons, small molecules, therapy",
author = "Hsieh, {Chung Han} and Li Li and Roeland Vanhauwaert and Nguyen, {Kong T.} and Davis, {Mary D.} and Guojun Bu and Wszolek, {Zbigniew K.} and Xinnan Wang",
note = "Funding Information: We thank M. Kim, Drs. W. Weis, S. Pokutta, and V. Bharat for technical support; the Neuroregeneration Lab at Mayo Clinic, NINDS, Michael J. Fox Foundation (MJFF), Coriell Institute, and Stanford ADRC Neuropathology and Biospecimens Core (P50 AG047366) for cell lines; Drs. A. Whitworth and K. Zinsmaier for antibodies; and Dr. S. Omlid for sourcing compounds. This work is supported by Klingenstein Fund (X.W.), CIRM (X.W.), NINDS (X.W. RO1NS089583 ), Archer Fund (X.W.), Stanford Parkinson{\textquoteright}s Disease Seed Grant (X.W.), Stanford SPARK (X.W.), Belgian American Education Foundation (R.V.), Sol Goldman Charitable Trust (Z.K.W.), Donald G. and Jodi P. Heeringa Family (Z.K.W.), Haworth Family Professorship in Neurodegenerative Diseases Fund (Z.K.W.), Albertson Parkinson's Research Foundation (Z.K.W.), and Mayo Clinic Center for Regenerative Medicine (M.D.D., Z.K.W., and G.B.). PPMI is funded by MJFF and funding partners, including AbbVie , Avid , Biogen , Bristol-Myers Squibb , COVANCE , GE Healthcare , Genentech , GlaxoSmithKline , Lilly , Lundbeck , Merck , Meso Scale Discovery , Pfizer , Piramal , Roche , Servier , and UCB . Funding Information: We thank M. Kim, Drs. W. Weis, S. Pokutta, and V. Bharat for technical support; the Neuroregeneration Lab at Mayo Clinic, NINDS, Michael J. Fox Foundation (MJFF), Coriell Institute, and Stanford ADRC Neuropathology and Biospecimens Core (P50 AG047366) for cell lines; Drs. A. Whitworth and K. Zinsmaier for antibodies; and Dr. S. Omlid for sourcing compounds. This work is supported by Klingenstein Fund (X.W.), CIRM (X.W.), NINDS (X.W. RO1NS089583), Archer Fund (X.W.), Stanford Parkinson's Disease Seed Grant (X.W.), Stanford SPARK (X.W.), Belgian American Education Foundation (R.V.), Sol Goldman Charitable Trust (Z.K.W.), Donald G. and Jodi P. Heeringa Family (Z.K.W.), Haworth Family Professorship in Neurodegenerative Diseases Fund (Z.K.W.), Albertson Parkinson's Research Foundation (Z.K.W.), and Mayo Clinic Center for Regenerative Medicine (M.D.D. Z.K.W. and G.B.). PPMI is funded by MJFF and funding partners, including AbbVie, Avid, Biogen, Bristol-Myers Squibb, COVANCE, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, and UCB. C.H. and L.L. performed experiments and made figures. R.V. assisted functional drug screen. K.N. performed virtual screen. M.D.D. G.B. and Z.K.W. recruited patients and collected fibroblasts. X.W. conceived and supervised the project, designed experiments, and wrote the paper with the assistance from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "3",
doi = "10.1016/j.cmet.2019.08.023",
language = "English (US)",
volume = "30",
pages = "1131--1140.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}