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Cell Metab. 2019 Sep 23. pii: S1550-4131(19)30497-8. doi: 10.1016/j.cmet.2019.08.023. [Epub ahead of print]

Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models.

Author information

1
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Atomwise Inc., San Francisco, CA 94105, USA.
3
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
4
Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
5
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: xinnanw@stanford.edu.

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' 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

PMID:
31564441
DOI:
10.1016/j.cmet.2019.08.023

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