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 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.This article has an associated First Person interview with the first author of the paper.

Alterations in α-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons.

Accumulation of α-synuclein is a pathological hallmark of Parkinson's disease (PD) and has been linked to reductions in neurite length and axonal degeneration of midbrain dopaminergic neurons. Mutations in SNCA, which encodes α-synuclein, and loss of function mutations in PTEN-induced putative kinase-1 (PINK1) cause familial PD. There is a need to identify the mechanisms by which α-synuclein overexpression and the loss of PINK1 induce neurodegeneration in PD. To do this, we employed rat ventral midbrain cultures to investigate the effects of overexpression of wildtype or mutant (A53T) α-synuclein, and of siRNA knockdown of PINK1, on neurite length and on mitochondrial and Golgi integrity. We found reduced neurite length and increased levels of both Golgi fragmentation and mitochondrial fission in response to overexpression of wildtype or mutant α-synuclein, and to PINK1 knockdown. Reductions in neurite length induced by these two PD risk genes were significantly correlated with increases in Golgi fragmentation and mitochondrial fission. Combined α-synuclein overexpression and PINK1 knockdown induced a greater reduction in neurite length and increase in Golgi fragmentation, than either alone. This study provides novel evidence that α-synuclein overexpression and PINK1 deletion converge to induce significant increases in Golgi fragmentation and mitochondrial fission in midbrain neurons, that are correlated with decreases in neurite length. This highlights the need for further studies on these converging mechanisms in dopaminergic neurodegeneration in PD.