S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson’s disease
Carmen R. SunicoTomohiro NakamuraEdward RockensteinMichael ManteAnthony AdameShing Fai ChanTraci Fang NewmeyerEliezer MasliahNobuki NakanishiStuart A. Lipton
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Abstract Background Mutations in the gene encoding parkin, a neuroprotective protein with dual functions as an E3 ubiquitin ligase and transcriptional repressor of p53, are linked to familial forms of Parkinson’s disease (PD). We hypothesized that oxidative posttranslational modification of parkin by environmental toxins may contribute to sporadic PD. Results We first demonstrated that S-nitrosylation of parkin decreased its activity as a repressor of p53 gene expression, leading to upregulation of p53. Chromatin immunoprecipitation as well as gel-shift assays showed that parkin bound to the p53 promoter, and this binding was inhibited by S-nitrosylation of parkin. Additionally, nitrosative stress induced apoptosis in cells expressing parkin, and this death was, at least in part, dependent upon p53. In primary mesencephalic cultures, pesticide-induced apoptosis was prevented by inhibition of nitric oxide synthase (NOS). In a mouse model of pesticide-induced PD, both S-nitrosylated (SNO-)parkin and p53 protein levels were increased, while administration of a NOS inhibitor mitigated neuronal death in these mice. Moreover, the levels of SNO-parkin and p53 were simultaneously elevated in postmortem human PD brain compared to controls. Conclusions Taken together, our data indicate that S-nitrosylation of parkin, leading to p53-mediated neuronal cell death, contributes to the pathophysiology of sporadic PD.Keywords:
S-Nitrosylation
Parkin is an E3 ubiquitin ligase belonging to the RING-between-RING family. Mutations in the Parkin-encoding gene PARK2 are associated with familial Parkinson's disease. Here, we investigate the interplay between Parkin and the inflammatory cytokine-induced ubiquitin-like modifier FAT10. FAT10 targets hundreds of proteins for degradation by the 26S proteasome. We show that FAT10 gets conjugated to Parkin and mediates its degradation in a proteasome-dependent manner. Parkin binds to the E2 enzyme of FAT10 (USE1), auto-FAT10ylates itself, and facilitates FAT10ylation of the Parkin substrate Mitofusin2 in vitro and in cells, thus identifying Parkin as a FAT10 E3 ligase. On mitochondrial depolarization, FAT10ylation of Parkin inhibits its activation and ubiquitin-ligase activity causing impairment of mitophagy progression and aggravation of rotenone-mediated death of dopaminergic neuronal cells. In conclusion, FAT10ylation inhibits Parkin and mitophagy rendering FAT10 a likely inflammation-induced exacerbating factor and potential drug target for Parkinson's disease.
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Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 and ATP13A2 Many pathogenic mutations of PARK2, which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis.
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Mutations of F-box protein 7 [FBXO7] and Parkin, two proteins related to Ubiquitin-Proteasome System [UPS], are implicated in the pathogenesis of Dopamine [DA] neuron degeneration in Parkinson's Disease [PD], possibly involving impairment of UPS and mitophagy. Parkin is a HECT/RING hybrid ubiquitin E3 ligase that physically receives ubiquitin on its catalytic centre and passes ubiquitin onto its substrates, whereas FBXO7 is an adaptor protein in Skp-Cullin-F-box [SCF] SCFFBXO7 ubiquitin E3 ligase complex to recognize substrates and mediate substrates ubiquitination by SCFFBXO7 E3 ligase. There are overlapping clinical features in Parkin and FBXO7 linked PD. One recent study demonstrates that FBXO7 can mediate mitochondrial translocation of Parkin under mitochondria impairment to initiate neuroprotective mitophagy. The signalling pathways of FBXO7 and Parkin may have complicated pathophysiological crosstalk, which should be implicated in PD pathogenesis and therapy. The FBXO7 may attract Parkin to impaired mitochondria to mediate ubiquitination of key substrates for mitophagy initiation. FBXO7 and Parkin may recognize each other as substrates reciprocally to promote their UPS degradation. Furthermore, FBXO7 may modulate Parkin E3 ligase activity. The aggregation-prone mutant FBXO7 has been shown to induce Parkin protein aggregation, which may lead to down regulation of available protective Parkin protein. Further studies are needed to decipher the complicated interactions between FBXO7 and Parkin.
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Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
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Parkin is mainly a cytosolic protein involved in a subset of Parkinson’s disease (PD) cases referred to as autosomal juvenile recessive forms of PD. Most studies have established as a dogma that parkin function could be resumed as an ubiquitin ligase activity. Accordingly, several cellular functions ascribed to parkin derive from its ability to ubiquitinate a series of proteins, thereby rendering them prone to proteasomal degradation. Several lines of data indicated that parkin could display antiapoptotic properties and we demonstrated that indeed, parkin could downregulate the p53-dependent pathway. However, we showed that such function remained independent of parkin’s ability to act as an ubiquitin ligase. Thus, we established that parkin repressed p53 transcription by physically interacting with its promoter. Here, we describe this novel parkin-associated transcription factor function and we speculate on putative additional transcriptional targets.
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Our finding that parkin, a ubiquitin E3 ligase, can be selectively S -nitrosylated by nitric oxide (NO) ([ 1 ][1]) was later confirmed by Yao et al . ([ 2 ][2]) and suggests a common pathogenic pathway in familial and idiopathic Parkinson's disease (PD). We found that nitrosylation of parkin
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