Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons.
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.
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.
Haisong
H
Jiang
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.
Sung-Ung
0000-0002-8393-2588
SU
Kang
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205.
Shuran
S
Zhang
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.
Senthilkumar
S
Karuppagounder
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.
Jinchong
J
Xu
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.
Yong-Kyu
0000-0003-0182-2279
YK
Lee
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.
Bong-Gu
0000-0003-0594-9509
BG
Kang
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.
Yunjong
0000-0003-0182-2279
Y
Lee
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.
Jianmin
0000-0003-4765-0812
J
Zhang
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205.
Olga
O
Pletnikova
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.
Juan C
JC
Troncoso
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.
Shelia
S
Pirooznia
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.
Shaida A
SA
Andrabi
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.
Valina L
0000-0002-2915-3970
VL
Dawson
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.
Ted M
0000-0002-6459-0893
TM
Dawson
D000368:Aged; D000369:Aged, 80 and over; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D011897:Random Allocation
D000697:Central Nervous System Stimulants; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D000661:Amphetamine
PGC-1α; dopamine neuron; mitochondria; neurodegeneration; substantia nigra