Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.
Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685;
Daniel A
DA
Stevens
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 446-746, South Korea;
Yunjong
Y
Lee
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Physiology, Ajou University School of Medicine, Suwon 443-721, Korea;
Ho Chul
HC
Kang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Age-Related and Brain Disease Research Center, Department of Neuroscience, Kyung Hee University, Seoul, 130-701, South Korea;
Byoung Dae
BD
Lee
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Well Aging Research Center, Samsung Advanced Institute of Technology, Yongin-si 446-712, Korea;
Yun-Il
YI
Lee
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685;
Aaron
A
Bower
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Haisong
H
Jiang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Sung-Ung
SU
Kang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Shaida A
SA
Andrabi
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Valina L
VL
Dawson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 446-746, South Korea; tdawson@jhmi.edu jshin24@skku.edu.
Joo-Ho
JH
Shin
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 tdawson@jhmi.edu jshin24@skku.edu.
Ted M
TM
Dawson
D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010101:Oxygen Consumption; D010300:Parkinson Disease / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D012097:Repressor Proteins; C557561:ZNF746 protein, mouse; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine
PARIS; Parkinson's disease; ZNF746; mitochondrial biogenesis; parkin