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

Akt signalling is central to cell survival, metabolism, protein and lipid homeostasis, and is impaired inParkinson'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. This article has an associated First Person interview with the first author of the paper.