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

Parkinson's disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth
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 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.
2041-4889
Chen, Rongmin
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Park, Han-A
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Mnatsakanyan, Nelli
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Niu, Yulong
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Licznerski, Pawel
cc1e5a51-e419-4570-a649-b365ed0f765a
Wu, Jing
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Miranda, Paige
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Graham, Morven
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Tang, Jack
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Boon, Agnita J. W.
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Cossu, Giovanni
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Mandemakers, Wim
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Bonifati, Vincenzo
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Smith, Peter J.S.
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Alavian, Kambiz N.
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Jonas, Elizabeth A.
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Chen, Rongmin
0eb6b4d3-782b-454f-9345-8591710436d9
Park, Han-A
6c3e2de0-909f-44d6-8ec9-61adab9d3c0f
Mnatsakanyan, Nelli
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Niu, Yulong
0bce249a-c838-48cf-b2b3-bf7fbe7aa270
Licznerski, Pawel
cc1e5a51-e419-4570-a649-b365ed0f765a
Wu, Jing
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Miranda, Paige
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Graham, Morven
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Tang, Jack
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Boon, Agnita J. W.
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Cossu, Giovanni
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Mandemakers, Wim
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Bonifati, Vincenzo
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Smith, Peter J.S.
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Alavian, Kambiz N.
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Jonas, Elizabeth A.
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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. and Jonas, Elizabeth A. (2019) Parkinson's disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth. Cell Death and Disease, 10, [469]. (doi:10.1038/s41419-019-1679-x).

Record type: Article

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.

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Accepted/In Press date: 19 May 2019
e-pub ahead of print date: 13 June 2019
Published date: June 2019

Identifiers

Local EPrints ID: 431886
URI: http://eprints.soton.ac.uk/id/eprint/431886
ISSN: 2041-4889
PURE UUID: 1caa6235-6695-4dd7-b637-51c3f30d6eb5
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 20 Jun 2019 16:30
Last modified: 16 Mar 2024 04:07

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Contributors

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

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