Cossu Giovanni

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

2019-06-13 , 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.

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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