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

Piston, Dominic, Alvarez-Erviti, Lydia, Bansal, Vikas , Gargano, Daniela, Yao, Zhi, Szabadkai, Gyorgy, Odell, Mark, Puno, M. Rhyan, Maple-Grødem, Jodie, Bjorkblom, Benny, Breuer, Peter, Kaut, Oliver, Larsen, Jan Petter, Bonn, Stefan, Geir Moller, Simon, Wullner, Ullrich, 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

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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, 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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