期刊
HUMAN MOLECULAR GENETICS
卷 26, 期 20, 页码 4028-4041出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx294
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资金
- Western Norway Regional Health Authority
- Medical Research Council (UK) [MR/M006646/1]
- Parkinson's UK [K-1507]
- Parkinson's UK
- NIHR
- German Centre for Neurodegenerative Diseases (DZNE)
- Medical Research Council (UK)
- MRC [MR/M006646/1] Funding Source: UKRI
- Medical Research Council [MR/M006646/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10237] Funding Source: researchfish
- Parkinson's UK [K-1507] Funding Source: researchfish
DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson's disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease.
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