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Parkinson’s disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth

2019; Springer Nature; Volume: 10; Issue: 6 Linguagem: Inglês

10.1038/s41419-019-1679-x

2041-4889

Rongmin Chen, Hana Park, Nelli Mnatsakanyan, Yulong Niu, Pawel Licznerski, Jing Wu, Paige Miranda, Morven Graham, Zeyu Tang, Agnita J.W. Boon, Giovanni Cossu, Wim Mandemakers, Vincenzo Bonifati, Peter J. Smith, Kambiz N. Alavian, Elizabeth A. Jonas,

Parkinson's Disease Mechanisms and Treatments

Abstract Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the F 1 F O ATP synthase β subunit. DJ-1’s interaction with the β subunit decreased mitochondrial uncoupling and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial uncoupling, and depolarized neuronal mitochondria. In mesencephalic DJ-1 KO cultures, there was a progressive loss of neuronal process extension. This was ameliorated by a pharmacological reagent, dexpramipexole, that binds to ATP synthase, closing a mitochondrial inner membrane leak and enhancing ATP synthase efficiency. ATP synthase c-subunit can form an uncoupling channel; we measured, therefore, ATP synthase F 1 (β subunit) and c-subunit protein levels. We found that ATP synthase β subunit protein level in the DJ-1 KO neurons was approximately half that found in their wild-type counterparts, comprising a severe defect in ATP synthase stoichiometry and unmasking c-subunit. We suggest that DJ-1 enhances dopaminergic cell metabolism and growth by its regulation of ATP synthase protein components.