1 Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35 Room 1A213, 35 Convent Drive, MSC 3708, Bethesda, MD 20892-3708, USA.
Brain. 2014 May;137(Pt 5):1304-22. doi: 10.1093/brain/awu002. Epub 2014 Feb 14.
The lysosomal enzyme glucocerebrosidase, encoded by the glucocerebrosidase gene, is involved in the breakdown of glucocerebroside into glucose and ceramide. Lysosomal build-up of the substrate glucocerebroside occurs in cells of the reticulo-endothelial system in patients with Gaucher disease, a rare lysosomal storage disorder caused by the recessively inherited deficiency of glucocerebrosidase. Gaucher disease has a broad clinical phenotypic spectrum, divided into non-neuronopathic and neuronopathic forms. Like many monogenic diseases, the correlation between clinical manifestations and molecular genotype is not straightforward. There is now a well-established clinical association between mutations in the glucocerebrosidase gene and the development of more prevalent multifactorial disorders including Parkinson's disease and other synucleinopathies. In this review we discuss recent studies advancing our understanding of the cellular relationship between glucocerebrosidase and α-synuclein, the potential impact of established and emerging therapeutics for Gaucher disease for the treatment of the synucleinopathies, and the role of lysosomal pathways in the pathogenesis of these neurodegenerative disorders.
溶酶体酶葡萄糖脑苷脂酶由葡萄糖脑苷脂酶基因编码，参与葡萄糖脑苷脂分解为葡萄糖和神经酰胺。葡萄糖脑苷脂在戈谢病患者的网状内皮系统细胞中积累，这是一种罕见的溶酶体贮积症，由葡萄糖脑苷脂酶的隐性遗传缺陷引起。戈谢病具有广泛的临床表型谱，分为非神经病变型和神经病变型。像许多单基因疾病一样，临床表现与分子基因型之间的相关性并不直接。目前，在葡萄糖脑苷脂酶基因的突变与更常见的多因素疾病（包括帕金森病和其他突触核蛋白病）的发展之间存在着明确的临床关联。在这篇综述中，我们讨论了最近的研究进展，这些研究加深了我们对葡萄糖脑苷脂酶和α-突触核蛋白之间细胞关系的理解，讨论了戈谢病现有和新兴治疗方法对突触核蛋白病治疗的潜在影响，以及溶酶体途径在这些神经退行性疾病发病机制中的作用。
