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

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 mutat...

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Veröffentlicht in:	Cell death & disease Jg. 10; H. 6; S. 469 - 12
Hauptverfasser:	Chen, Rongmin, Park, Han-A, Mnatsakanyan, Nelli, Niu, Yulong, Licznerski, Pawel, Wu, Jing, Miranda, Paige, Graham, Morven, Tang, Jack, Boon, Agnita J. W., Cossu, Giovanni, Mandemakers, Wim, Bonifati, Vincenzo, Smith, Peter J. S., Alavian, Kambiz N., Jonas, Elizabeth A.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 13.06.2019 Springer Nature B.V
Schlagworte:	13/31 14/19 14/28 42/109 631/378/1689 631/80/304 96/106 Animals Antibodies ATP synthase Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Dopamine receptors Dopaminergic Neurons - metabolism Gene Expression Humans Immunology Life Sciences Membrane Potential, Mitochondrial - genetics Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondrial Membranes - metabolism Mitochondrial Proton-Translocating ATPases - genetics Mitochondrial Proton-Translocating ATPases - metabolism Movement disorders Mutation Neurodegenerative diseases PARK7 protein Parkinson's disease Protein Binding Protein Deglycase DJ-1 - genetics Protein Deglycase DJ-1 - metabolism Proteins Rats, Sprague-Dawley Stoichiometry
ISSN:	2041-4889, 2041-4889
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-019-1679-x