@article{25e9c2670d804c22b8ab6ad6a1586573,
title = "Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PARKIN-Deficient Human Dopamine Neurons",
abstract = "Mutations and loss of activity in PARKIN, an E3 ubiquitin ligase, play a role in the pathogenesis of Parkinson's disease (PD). PARKIN regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. Defects in mitophagy have been hypothesized to play a predominant role in the loss of dopamine (DA) neurons in PD. Here, we show that although there are defects in mitophagy in human DA neurons lacking PARKIN, the mitochondrial deficits are primarily due to defects in mitochondrial biogenesis that are driven by the upregulation of PARIS and the subsequent downregulation of PGC-1α. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without affecting the deficits in mitophagy. These results highlight the importance mitochondrial biogenesis versus mitophagy in the pathogenesis of PD due to inactivation or loss of PARKIN in human DA neurons.",
keywords = "PARIS, PARKIN, PGC-1α, Parkinson's disease, ZNF746, dopamine, human IPSC, isogenic, mitochondrial biogenesis, mitophagy",
author = "Manoj Kumar and Jes{\'u}s Acevedo-Cintr{\'o}n and Aanishaa Jhaldiyal and Hu Wang and Andrabi, {Shaida A.} and Stephen Eacker and Karuppagounder, {Senthilkumar S.} and Saurav Brahmachari and Rong Chen and Hyesoo Kim and Ko, {Han Seok} and Dawson, {Valina L.} and Dawson, {Ted M.}",
note = "Funding Information: This work was supported by grants from the NIH/ NINDS NS38377 , and the JPB Foundation . The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through their direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation's Parkinson's Disease Programs M-1, M-2, H-2014. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. We thank the Dawson lab personnel for helpful suggestions. Funding Information: This work was supported by grants from the NIH/NINDS NS38377, and the JPB Foundation. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through their direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation's Parkinson's Disease Programs M-1, M-2, H-2014. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. We thank the Dawson lab personnel for helpful suggestions. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = sep,
day = "8",
doi = "10.1016/j.stemcr.2020.07.013",
language = "English (US)",
volume = "15",
pages = "629--645",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "3",
}