S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson's Disease Model

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 22; p. 3682
• Main Authors: Kim, Hanna, Lee, Ji-Yeong, Park, Soo Jeong, Kwag, Eunsang, Kim, Jihye, Shin, Joo-Ho
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.11.2022; MDPI
• Subjects: Alzheimer's disease; Animals; Antibodies; Apoptosis; Arginine; Copy number; Diagnosis; Dopamine receptors; Dopaminergic Neurons; Fibrils; Genetic aspects; Mice; Mice, Knockout; Mitochondrial DNA; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurotoxicity; Nitric oxide; Nitric-oxide synthase; nitrosative stress; PARIS/ZNF746; Parkinson Disease; Parkinson's disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Peroxisome proliferator-activated receptors; PGC-1α; Proteins; Reagents; S-nitrosylation; Substantia Nigra; Synuclein; Transcription Factors; South Korea; United States > US; Germany; nitrosative stress; PGC-1α; PARIS/ZNF746; Parkinson’s disease; S-nitrosylation
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11223682

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.