Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Nat Rev Neurol. 2024 Sep;20(9):526-540. doi: 10.1038/s41582-024-00999-z. Epub 2024 Aug 6.
An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease (PD). Gaucher disease is a lysosomal storage disorder resulting from an inherited deficiency of the enzyme glucocerebrosidase, encoded by GBA1, which hydrolyses the glycosphingolipids glucosylceramide and glucosylsphingosine. The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. PD occurs more frequently in people heterozygous for Gaucher GBA1 mutations, and 3-25% of people with Parkinson disease carry a GBA1 variant. However, only a small percentage of individuals with GBA1 variants develop parkinsonism, suggesting that the penetrance is low. Despite over a decade of intense research in this field, including clinical and radiological evaluations, genetic studies and investigations using model systems, the mechanism underlying GBA1-PD is still being pursued. Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. Furthermore, different therapeutic strategies considered or developed for Gaucher disease can now inform drug development for PD.
神经退行性疾病领域的一个令人兴奋的发展是罕见的单基因疾病戈谢病与常见的复杂疾病帕金森病（PD）之间的关联。戈谢病是一种溶酶体贮积症，由 GBA1 编码的酶葡糖脑苷脂酶的遗传性缺乏引起，该酶水解糖鞘脂葡萄糖脑苷脂和葡萄糖神经酰胺。戈谢病中罕见亚组个体帕金森病的观察首先引起了人们对葡糖脑苷脂酶缺乏在 PD 发病机制中的作用的关注。杂合 GBA1 突变的人患帕金森病的频率更高，3-25%的帕金森病患者携带 GBA1 变体。然而，只有一小部分携带 GBA1 变体的个体发展为帕金森病，这表明外显率较低。尽管在这一领域进行了十多年的密集研究，包括临床和影像学评估、遗传研究以及使用模型系统的研究，但 GBA1-PD 的机制仍在研究中。这种关联的研究结果强调了溶酶体途径在帕金森病中的作用。此外，目前用于戈谢病的不同治疗策略可以为 PD 的药物开发提供信息。
