PLA2G6基因突变可导致常染色体隐性遗传早发帕金森综合征（AREP），主要致病机制涉及线粒体功能障碍和铁离子沉积。有研究发现在PLA2G6突变患者和PLA2G6基因敲除小鼠的脑组织中，均证实有广泛α-synuclein（+）路易小体存在，因此推测PLA2G6基因突变可导致α-synuclein病理性聚集，且具体机制不明。前期工作中，我们在一AREP家系中，发现PLA2G6基因错义突变（D331Y），功能研究显示该突变后的PLA2G6蛋白酶活性下降70%。目前我们已成功构建PLA2G6基因敲除和D331Y敲入小鼠模型。本研究拟在前期研究的基础上，通过离体细胞和在体小鼠模型，探讨PLA2G6基因突变对α-synuclein病理性聚集的影响，并从线粒体、铁和α-synuclein蛋白降解方面阐明作用机制。本项目有助于深入探究帕金森病不同致病基因之间共同的作用靶点，为防治提供新思路和新视角。

Mutations in the PLA2G6 gene have been reported in autosomal recessive early-onset parkinsonism (AREP). The main pathogenic mechanisms are mitochondrial impairment and iron accumulation. Previously, it was reported that widespread α-synuclein-positive Lewy bodies were found in the brain of both patients with PLA2G6 gene mutations and PLA2G6 knockout mouses, which is suggested that there is a link between PLA2G6 gene and α-synuclein aberrant accumulation. But so far the exact mechanisms remain unclear. In previous studies, We discovered a homozygousPLA2G6 p.D331Y mutation in AREP. Compared to the wild-type PLA2G6 protein, the mutated p.D331Y protein showed a 70% reduction in enzyme activity. At present, we have successfully constructed PLA2G6 gene knockout and D331Y knock in mouse model. In this study, we plan to verify the effects of reduction in PLA2G6 enzyme activity on aberrant accumulation of α-synuclein in vitro cell models and in vivo mouse models. And then, we will further clarify the possible mechanisms through mitochondrial impairment, increased the ion load and paralysed protein degradation. This project will be helpful to explore the common targets or substrates between different pathogenic genes of Parkinson's disease (PD), and to provide new ideas and new insights for prevention and therapeutic strategies in PD.