Wang Dong-Xia, Xie Jun-Xia, Song Ning
Department of Physiology and Pathophysiology, Institute of Brain Science and Disease, Medical College of Qingdao University, Qingdao 266071, China.
Sheng Li Xue Bao. 2018 Jun 25;70(3):294-300.
Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the intraneuronal Lewy bodies in this area. Genetic mutations in PD pathogenesis have been explored and better understood in recent years. GBA variants are now considered to be the single largest risk factor for PD. Gaucher disease (GD) is a lysosomal storage disorder disease and an inherited deficiency of lysosomal glucocerebrosidase (GCase) arising from mutations in the gene GBA. A group of patients with GD exhibit parkinsonian symptoms, meanwhile, GBA mutations are more frequently observed in patients with PD. These lines of evidence suggest a close relationship between GBA mutations and PD. GBA mutations are associated with an earlier onset age and a distinct cognitive decline in PD. GCase loss-of-function caused by GBA mutations interferes with the degradation of α-synuclein, and α-synuclein pathology in turn inhibits normal GCase function in PD, which forms a vicious cycle. However, the exact mechanisms for this bidirectional pathogenic loop have not to be fully elucidated. In this review, we summarize the current understandings on the potential link between GBA mutations and PD pathogenesis, which may show novel insights into PD etiology and therapeutics.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质中多巴胺能神经元的退化以及该区域神经元内的路易小体。近年来，人们对帕金森病发病机制中的基因突变进行了探索并有了更深入的了解。GBA 变异现在被认为是帕金森病的单一最大风险因素。戈谢病（GD）是一种溶酶体贮积症，是由于 GBA 基因突变导致的溶酶体葡萄糖脑苷脂酶（GCase）遗传性缺乏。一组戈谢病患者表现出帕金森症状，同时，在帕金森病患者中更频繁地观察到 GBA 突变。这些证据表明 GBA 突变与帕金森病之间存在密切关系。GBA 突变与帕金森病发病年龄较早和明显的认知衰退有关。GBA 突变导致的 GCase 功能丧失会干扰α-突触核蛋白的降解，而α-突触核蛋白病变反过来又会抑制帕金森病中正常的 GCase 功能，从而形成恶性循环。然而，这种双向致病循环的确切机制尚未完全阐明。在这篇综述中，我们总结了目前对 GBA 突变与帕金森病发病机制之间潜在联系的理解，这可能为帕金森病的病因学和治疗提供新的见解。
