The Parkinson's disease gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3

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dc.contributor.authorFurlong, Rachel M.
dc.contributor.authorLindsay, Andrew J.
dc.contributor.authorAnderson, Karen E.
dc.contributor.authorHawkins, Phillip T.
dc.contributor.authorSullivan, Aideen M.
dc.contributor.authorO'Neill, Cora
dc.contributor.funderIrish Research Council for Science, Engineering and Technologyen
dc.contributor.funderBiotechnology and Biological Sciences Research Councilen
dc.date.accessioned2020-03-05T16:31:52Z
dc.date.available2020-03-05T16:31:52Z
dc.date.issued2019-10-22
dc.date.updated2020-03-05T15:45:43Z
dc.description.abstractAkt signalling is central to cell survival, metabolism, protein and lipid homeostasis, and is impaired in Parkinson's disease (PD). Akt activation is reduced in the brain in PD, and by many PD-causing genes, including PINK1 This study investigated the mechanisms by which PINK1 regulates Akt signalling. Our results reveal for the first time that PINK1 constitutively activates Akt in a PINK1-kinase dependent manner in the absence of growth factors, and enhances Akt activation in normal growth medium. In PINK1-modified MEFs, agonist-induced Akt signalling failed in the absence of PINK1, due to PINK1 kinase-dependent increases in PI(3,4,5)P3 at both plasma membrane and Golgi being significantly impaired. In the absence of PINK1, PI(3,4,5)P3 levels did not increase in the Golgi, and there was significant Golgi fragmentation, a recognised characteristic of PD neuropathology. PINK1 kinase activity protected the Golgi from fragmentation in an Akt-dependent fashion. This study demonstrates a new role for PINK1 as a primary upstream activator of Akt via PINK1 kinase-dependent regulation of its primary activator PI(3,4,5)P3, providing novel mechanistic information on how loss of PINK1 impairs Akt signalling in PD.en
dc.description.sponsorshipIrish Research Council for Science, Engineering and Technology (Government of Ireland Postgraduate Scholarship Programme grant number GOIPG/2015/3467); Biotechnology and Biological Research Council ((BBSRC) UK grant number BB/P013384/1)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationFurlong, R. M., Lindsay, A., Anderson, K. E., Hawkins, P. T., Sullivan, A. M. and O'Neill, C. (2019) 'The Parkinson's disease gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3', Journal of Cell Science, 132(20), jcs233221, doi: 10.1242/jcs.233221en
dc.identifier.doi10.1242/jcs.233221en
dc.identifier.endpage21en
dc.identifier.issn1477-9137
dc.identifier.issued20en
dc.identifier.journaltitleJournal of Cell Scienceen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/9727
dc.identifier.volume132en
dc.language.isoenen
dc.publisherThe Company of Biologistsen
dc.relation.urihttps://jcs.biologists.org/content/132/20/jcs233221
dc.rights© 2019. Published by The Company of Biologists Ltd.en
dc.subjectAkten
dc.subjectNeurodegenerationen
dc.subjectParkinson's diseaseen
dc.subjectPINK1en
dc.subjectPIP3en
dc.titleThe Parkinson's disease gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3en
dc.typeArticle (peer-reviewed)en
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