@article{343c1d48036142b296d6c8917392a456,
title = "Deubiquitinase CYLD acts as a negative regulator of dopamine neuron survival in Parkinson{\textquoteright}s disease",
abstract = "Mutations in PINK1 and parkin highlight the mitochondrial axis of Parkinson{\textquoteright}s disease (PD) pathogenesis. PINK1/ parkin regulation of the transcriptional repressor PARIS bears direct relevance to dopamine neuron survival through augmentation of PGC-1α–dependent mitochondrial biogenesis. Notably, knockout of PARIS attenuates dopaminergic neurodegeneration in mouse models, indicating that interventions that prevent dopaminergic accumulation of PARIS could have therapeutic potential in PD. To this end, we have identified the deubiquitinase cylindromatosis (CYLD) to be a regulator of PARIS protein stability and proteasomal degradation via the PINK1/ parkin pathway. Knockdown of CYLD in multiple models of PINK1 or parkin inactivation attenuates PARIS accumulation by modulating its ubiquitination levels and relieving its repressive effect on PGC-1α to promote mitochondrial biogenesis. Together, our studies identify CYLD as a negative regulator of dopamine neuron survival, and inhibition of CYLD may potentially be beneficial in PD by lowering PARIS levels and promoting mitochondrial biogenesis.",
author = "Pirooznia, {Sheila K.} and Hu Wang and Nikhil Panicker and Manoj Kumar and Stewart Neifert and Dar, {Mohamad Aasif} and Evan Lau and Kang, {Bong Gu} and Javier Redding-Ochoa and Troncoso, {Juan C.} and Dawson, {Valina L.} and Dawson, {Ted M.}",
note = "Funding Information: We thank G. Mosialos, Aristotle University of Thessaloniki, Greece for providing Exon 9 floxed CYLD mice and F. Ikeda, Institute of Molecular Biotechnology, Vienna, Austria for providing Drosophila plasmid CYLD constructs. Funding: This work was supported by grants from the NIH/NINDS NS38377 and K99AG066862 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 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{\textquoteright}s Parkinson{\textquoteright}s Disease Programs M-1, M-2, M-2014, and H-2104. Author contributions: Conceptualization: S.K.P., V.L.D., and T.M.D. Methodology: S.K.P., H.W., M.K., V.L.D., and T.M.D. Formal analysis: S.K.P. Investigation: S.K.P., H.W., N.P., M.K., S.N., M.A.D., E.L., and B.G.K. Writing—original draft: S.K.P., V.L.D., and T.M.D. Writing—review and editing: S.K.P., H.W., N.P., M.K., S.N., M.D., E.L., B.G.K., J.C.T., V.L.D., and T.M.D. Reagents and materials: J.R.-O., J.C.T., V.L.D., and T.M.D. Funding acquisition: V.L.D. and T.M.D. Supervision: V.L.D. and T.M.D. All authors have read and approved the final manuscript. Competing interests: The value of patents owned by Valted LLC could be affected by the study described in this article. V.L.D. and T.M.D. are founders of Valted, LLC and hold ownership equity interest in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The Exon 9 floxed CYLD mice can be provided by Aristotle University of Thessaloniki, Greece pending scientific review and a completed material transfer agreement. Requests for the Exon 9 floxed CYLD mice should be submitted to G. Mosialos. Requests for other materials should be submitted to T.M.D. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
doi = "10.1126/sciadv.abh1824",
language = "English (US)",
volume = "8",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "13",
}