Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons

Haisong Jiang; Sung-Ung Kang; Shuran Zhang; Senthilkumar Karuppagounder; Jinchong Xu; Yong-Kyu Lee; Bong-Gu Kang; Yunjong Lee; Jianmin Zhang; Olga Pletnikova; Juan C Troncoso; Shelia Pirooznia; Shaida A Andrabi; Valina L Dawson; Ted M Dawson

doi:10.1523/ENEURO.0183-16.2016

Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons

eNeuro. 2016 Sep 2;3(4):ENEURO.0183-16.2016. doi: 10.1523/ENEURO.0183-16.2016. eCollection 2016 Jul-Aug.

Authors

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685.
² Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685.
⁵ Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205.
⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
⁷ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.

Abstract

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α) in PD and in animal or cellular models of PD. The role of PGC-1α in the function and survival of substantia nigra pars compacta (SNpc) dopamine neurons is not clear. Here we find that there are four different PGC-1α isoforms expressed in SH-SY5Y cells, and these four isoforms are expressed across subregions of mouse brain. Adult conditional PGC-1α knock-out mice show a significant loss of dopaminergic neurons that is accompanied by a reduction of dopamine in the striatum. In human PD postmortem tissue from the SNpc, there is a reduction of PGC-1α isoforms and mitochondria markers. Our findings suggest that all four isoforms of PGC-1α are required for the proper expression of mitochondrial proteins in SNpc DA neurons and that PGC-1α is essential for SNpc DA neuronal survival, possibly through the maintenance of mitochondrial function.

Keywords: PGC-1α; dopamine neuron; mitochondria; neurodegeneration; substantia nigra.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Amphetamine / pharmacology
Animals
Cell Death / physiology
Central Nervous System Stimulants / pharmacology
Corpus Striatum / drug effects
Corpus Striatum / metabolism
Corpus Striatum / pathology
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism*
Dopaminergic Neurons / pathology*
Female
Gene Knockout Techniques
Humans
Male
Mice, Knockout
Mitochondria / metabolism
Mitochondria / pathology
Motor Activity / drug effects
Motor Activity / physiology
Parkinson Disease / metabolism
Parkinson Disease / pathology
Pars Compacta / drug effects
Pars Compacta / metabolism
Pars Compacta / pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
Protein Isoforms
Random Allocation

Substances

Central Nervous System Stimulants
PPARGC1A protein, human
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Protein Isoforms
Amphetamine

Grants and funding

P50 AG005146/AG/NIA NIH HHS/United States