Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most important genetic risk factor for Parkinson disease (PD). GCase activity is also decreased in sporadic PD brains and with normal ageing. Loss of GCase activity impairs the autophagy lysosomal pathway resulting in increased α-synuclein (α-syn) levels. Furthermore, elevated α-syn results in decreased GCase activity. Although the role of α-syn in PD remains unclear, evidence indicates that aggregated α-syn fibrils are a pathogenic species in PD, passing between neurons and inducing endogenous native α-syn to aggregate; spreading pathology through the brain. We have investigated if preformed α-syn fibrils (PFFs) impair GCase activity in mouse cortical neurons and differentiated dopaminergic cells, and whether GCase deficiency in these models increased the transfer of α-syn pathology to naïve cells. Neurons treated with PFFs induced endogenous α-syn to become insoluble and phosphorylated at Ser129 to a greater extent than monomeric α-syn-treatment. PFFs, but not monomeric α-syn, inhibited lysosomal GCase activity in these cells and induced the unfolded protein response. Neurons in which GCase was inhibited by conduritol β-epoxide did not increase the amount of insoluble monomeric α-syn or its phosphorylation status. Instead the release of α-syn fibrils from GCase deficient cells was significantly increased. Co-culture studies showed that the transfer of α-syn pathology to naïve cells was greater from GCase deficient cells. This study suggests that GCase deficiency increases the spread of α-syn pathology and likely contributes to the earlier age of onset and increased cognitive decline associated with GBA-PD.

中文翻译：

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葡糖脑苷脂酶缺乏促进α-突触核蛋白原纤维从培养的神经元中释放。

GBA中的突变编码溶酶体酶葡糖脑苷脂酶（GCase）的基因是帕金森病（PD）最重要的遗传风险因素。GCase 活性在散发性 PD 大脑和正常衰老中也会降低。GCase 活性的丧失会损害自噬溶酶体途径，导致 α-突触核蛋白 (α-syn) 水平增加。此外，α-syn 升高会导致 GCase 活性降低。尽管 α-syn 在 PD 中的作用尚不清楚，但有证据表明聚集的 α-syn 原纤维是 PD 的致病物质，在神经元之间传递并诱导内源性天然 α-syn 聚集；通过大脑传播病理。我们已经研究了预先形成的 α-syn 原纤维 (PFF) 是否会损害小鼠皮层神经元和分化的多巴胺能细胞中的 GCase 活性，以及这些模型中的 GCase 缺陷是否增加了 α-syn 病理向幼稚细胞的转移。与单体 α-syn 处理相比，用 PFF 处理的神经元在更大程度上诱导内源性 α-syn 变得不溶并在 Ser129 处磷酸化。PFFs，但不是单体 α-syn，抑制这些细胞中的溶酶体 GCase 活性并诱导未折叠蛋白反应。GCase 被 conduritol β-epoxide 抑制的神经元不会增加不溶性单体 α-syn 的数量或其磷酸化状态。相反，GCase 缺陷细胞中 α-syn 原纤维的释放显着增加。共培养研究表明，α-syn 病理学从 GCase 缺陷细胞转移到幼稚细胞的可能性更大。GBA- PD。