DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis

Piston, Dominic and Alvarez-Erviti, Lydia and Bansal, Vikas and Gargano, Daniela and Yao, Zhi and Szabadkai, Gyorgy and Odell, Mark and Puno, M. Rhyan and Maple-Grødem, Jodie and Bjorkblom, Benny and Breuer, Peter and Kaut, Oliver and Larsen, Jan Petter and Bonn, Stefan and Geir Moller, Simon and Wullner, Ullrich and Schapira, Anthony H. V. and Gegg, Matthew E. (2017) DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis. Human Molecular Genetics, 26 (20). pp. 4028-4041. ISSN 0964-6906

Full content URL: https://academic.oup.com/hmg/article/26/20/4028/40...

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Abstract

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.

Additional Information:A correction has been published: Human Molecular Genetics, Volume 27, Issue 3, 1 February 2018, Pages 576, https://doi.org/10.1093/hmg/ddx425 Open Access paid by MRC
Keywords:norepinephrine, catecholamines, oxidation, homeostasis, molecular mass, messenger rna, rna sequence analysis, brain rna, parkinson disease 7, autosomal recessive early-onset, complex
Subjects:B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science > School of Life Sciences
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ID Code:30684
Deposited On:27 Feb 2018 12:55

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