Department of Clinical Neuroscience, Institute of Neurology, University College London, UK.
FEBS J. 2018 Oct;285(19):3591-3603. doi: 10.1111/febs.14393. Epub 2018 Feb 19.
GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of α-synuclein. A hallmark of PD is the presence of intraneuronal protein inclusions called Lewy bodies, which are composed mainly of α-synuclein. Cellular and animal models of GCase deficiency result in lysosomal dysfunction, and in particular the autophagy lysosome pathway, resulting in the accumulation of α-synuclein. Some forms of mutant GCase unfold in the endoplasmic reticulum activating the unfolded protein response, which might also contribute to PD pathogenesis. It has also been suggested that accumulation of GCase substrates glucosylceramide/glucosylsphingosine may contribute to GBA-PD pathogenesis. Mitochondrial dysfunction and neuroinflammation are associated with GCase deficiency and have also been implicated in the aetiology of PD. This review discusses these points and highlights potential treatments that might be effective in treating GCase deficiency in PD.
GBA 编码溶酶体酶葡萄糖脑苷脂酶（GCase），一种参与鞘脂代谢的酶。GBA 基因的突变是导致帕金森病（PD）的最重要危险因素之一，至少占所有 PD 病例的 5%。此外，在散发性 PD 脑中发现 GCase 活性丧失。溶酶体功能障碍被认为在 PD 的发病机制中起主要作用，特别是对α-突触核蛋白代谢的影响。PD 的一个标志是存在称为路易体的神经元内蛋白包涵体，其主要由α-突触核蛋白组成。GCase 缺乏的细胞和动物模型导致溶酶体功能障碍，特别是自噬溶酶体途径，导致α-突触核蛋白的积累。一些形式的突变 GCase 在内质网中展开，激活未折叠蛋白反应，这也可能导致 PD 的发病机制。也有人认为，GCase 底物葡萄糖脑苷脂/葡萄糖鞘氨醇的积累可能有助于 GBA-PD 的发病机制。线粒体功能障碍和神经炎症与 GCase 缺乏有关，也与 PD 的病因有关。这篇综述讨论了这些观点，并强调了可能对治疗 PD 中的 GCase 缺乏有效的潜在治疗方法。
