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

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

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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 F1FO 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 F1 (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.

Original languageEnglish (US)
Article number469
JournalCell Death and Disease
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2019

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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