Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 37, Pages 11696-11701Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1500624112
Keywords
Parkinson's disease; ZNF746; mitochondrial biogenesis; PARIS; parkin
Categories
Funding
- NIH/National Institute of Neurological Disorders and Stroke [NS38377]
- JPB Foundation
- National Research Foundation [2012R1A1A1012435]
- Korean Ministry of Science, Information, Communications, and Technology (ICT) and Future Planning (MSIP)
- Samsung Biomedical Research Institute [SMX1132521]
- National Research Foundation of Korea [2012R1A1A1012435] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-1 alpha. 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-1 alpha-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.
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