Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Daniel A Stevens; Yunjong Lee; Ho Chul Kang; Byoung Dae Lee; Yun-Il Lee; Aaron Bower; Haisong Jiang; Sung-Ung Kang; Shaida A Andrabi; Valina L Dawson; Joo-Ho Shin; Ted M Dawson

doi:10.1073/pnas.1500624112

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11696-701. doi: 10.1073/pnas.1500624112. Epub 2015 Aug 31.

Authors

Daniel A Stevens¹, Yunjong Lee², Ho Chul Kang³, Byoung Dae Lee⁴, Yun-Il Lee⁵, Aaron Bower⁶, Haisong Jiang⁷, Sung-Ung Kang⁷, Shaida A Andrabi⁸, Valina L Dawson⁹, Joo-Ho Shin¹⁰, Ted M Dawson¹¹

Affiliations

¹ 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;
² 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;
³ 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;
⁴ 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;
⁵ 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;
⁶ 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;
⁷ 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;
⁸ 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;
⁹ 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;
¹⁰ 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.
¹¹ 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.

Abstract

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.

Keywords: PARIS; Parkinson's disease; ZNF746; mitochondrial biogenesis; parkin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / embryology
Brain / metabolism
Cell Death
Cell Line, Tumor
Dopamine / metabolism
Dopaminergic Neurons / metabolism
Gene Expression Regulation
Green Fluorescent Proteins / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism*
Neurons / metabolism
Oxygen Consumption
Parkinson Disease / metabolism
Repressor Proteins / physiology
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / physiology*

Substances

Repressor Proteins
ZNF746 protein, mouse
Green Fluorescent Proteins
Ubiquitin-Protein Ligases
parkin protein
Dopamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding