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.

中文翻译：

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帕金森氏病基因PINK1通过磷脂PI（3,4,5）P3的PINK1激酶依赖性调节激活Akt。

Akt信号传导对细胞存活，代谢，蛋白质和脂质体内稳态至关重要，并且在帕金森氏病（PD）中受损。PD以及许多导致PD的基因（包括PINK1）在大脑中的Akt激活都减少了。这项研究调查了PINK1调节Akt信号传导的机制。我们的结果首次揭示了PINK1在不存在生长因子的情况下以PINK1激酶依赖性方式组成性激活Akt，并增强了正常生长培养基中的Akt激活。在PINK1修饰的MEF中，在没有PINK1的情况下，激动剂诱导的Akt信号传导失败，这是由于质膜和高尔基体上的PINK1激酶依赖性PI（3,4,5）P3升高所致。在没有PINK1的情况下，高尔基体中PI（3,4,5）P3的水平没有增加，并且高尔基体明显分裂，PD神经病理学的公认特征。PINK1激酶活性可保护高尔基体免受Akt依赖性方式的断裂。这项研究证明了PINK1作为Akt的主要上游激活剂的新作用，通过其主要激活因子PI（3,4,5）P3的PINK1激酶依赖性调节，提供了有关PINK1缺失如何损害PD中Akt信号传导的新机制信息。本文与论文的第一作者进行了第一人称访谈。