S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson’s Disease Modelopen access
- Authors
- Kim, H.[Kim, H.]; Lee, J.-Y.[Lee, J.-Y.]; Park, S.J.[Park, S.J.]; Kwag, E.[Kwag, E.]; Kim, J.[Kim, J.]; Shin, J.-H.[Shin, J.-H.]
- Issue Date
- Nov-2022
- Publisher
- MDPI
- Keywords
- nitrosative stress; PARIS/ZNF746; Parkinson’s disease; PGC-1α; S-nitrosylation
- Citation
- Cells, v.11, no.22
- Indexed
- SCIE
SCOPUS
- Journal Title
- Cells
- Volume
- 11
- Number
- 22
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/105749
- DOI
- 10.3390/cells11223682
- ISSN
- 2073-4409
- Abstract
- Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson’s disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the insoluble fraction, leading to the sequestration of PGC-1α into insoluble deposits. The mislocalization of PGC-1α in the insoluble fraction was observed in S-nitrosocysteine-treated PARIS knockout (KO) cells overexpressing PARIS WT but not S-nitrosylation deficient C265S mutant, indicating that insolubility of PGC-1α is SNO-PARIS-dependent. In the sporadic PD model, α-synuclein preformed fibrils (α-syn PFFs)-injected mice, we found an increase in PARIS, SNO-PARIS, and insoluble sequestration of PGC-1α in substantia nigra (SN), resulting in the reduction of mitochondrial DNA copy number and ATP concentration that were restored by N(ω)-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor. To assess the dopaminergic (DA) neuronal toxicity by SNO-PARIS, lentiviral PARIS WT, C265S, and S-nitrosylation mimic C265W was injected into the SN of either PBS- or α-syn PFFs-injected mice. PARIS WT and C265S caused DA neuronal death to a comparable extent, whereas C265W caused more severe DA neuronal loss in PBS-injected mice. Interestingly, there was synergistic DA loss in both lenti-PARIS WT and α-syn PFFs-injected mice, indicating that SNO-PARIS by α-syn PFFs contributes to the DA toxicity in vivo. Moreover, α-syn PFFs-mediated increment of PARIS, SNO-PARIS, DA toxicity, and behavioral deficits were completely nullified in neuronal NOS KO mice, suggesting that modulation of NO can be a therapeutic for α-syn PFFs-mediated neurodegeneration. © 2022 by the authors.
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Collections - Medicine > Department of Medicine > 1. Journal Articles
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