Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder

Wei Lu, Senthilkumar S. Karuppagounder, Danielle A. Springer, Michele D. Allen, Lixin Zheng, Brittany Chao, Yan Zhang, Valina L. Dawson, Ted M. Dawson and Michael Lenardo ()
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Wei Lu: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Senthilkumar S. Karuppagounder: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Danielle A. Springer: Murine Phenotyping Core, National Heart, Lung, and Blood Institute, National Institutes of Health
Michele D. Allen: Murine Phenotyping Core, National Heart, Lung, and Blood Institute, National Institutes of Health
Lixin Zheng: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Brittany Chao: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Yan Zhang: Molecular Mechanism of Apoptosis Section, Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health
Valina L. Dawson: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Ted M. Dawson: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Michael Lenardo: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Mitophagy is a specialized form of autophagy that selectively disposes of dysfunctional mitochondria. Delineating the molecular regulation of mitophagy is of great importance because defects in this process lead to a variety of mitochondrial diseases. Here we report that mice deficient for the mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5), displayed a Parkinson’s-like movement phenotype. We determined biochemically that PGAM5 is required for the stabilization of the mitophagy-inducing protein PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration and mild dopamine loss in vivo. Our data indicate that PGAM5 is a regulator of mitophagy essential for mitochondrial turnover and serves a cytoprotective function in dopaminergic neurons in vivo. Moreover, PGAM5 may provide a molecular link to study mitochondrial homeostasis and the pathogenesis of a movement disorder similar to Parkinson’s disease.

Date: 2014
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DOI: 10.1038/ncomms5930

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