GBA突变与帕金森病的研究进展
王冬霞, 谢俊霞, 宋宁^*
青岛大学基础医学院生理学与病理生理学系，脑科学与疾病研究院，青岛 266071
摘要
帕金森病(Parkinson’s disease, PD)是一种黑质致密部多巴胺能神经元广泛变性，以及弥漫性路易体沉积的常见神经退行性疾病。PD发病的遗传因素不可忽视。研究表明，GBA突变是PD发病最大的遗传风险因素。戈谢病(Gaucher disease, GD)是由GBA突变引起其编码的葡萄糖脑苷脂酶(glucocerebrosidase, GCase)功能缺失导致的一种溶酶体储存障碍疾病。部分GD病例出现PD的临床表现，且PD病例中GBA突变的频率明显增加，提示了GBA突变与PD的密切联系。携带GBA突变的PD病例发病更早，且GBA突变能够增加PD病例认知障碍的风险。虽然大量研究提示了GBA突变导致的GCase功能障碍干扰α-突触核蛋白的降解，而在PD疾病状态下异常的α-突触核蛋白可抑制正常的GCase功能并由此导致恶性循环，但关于GBA突变与α-突触核蛋白相互作用的确切机制仍未完全明确。本综述旨在总结GBA突变与PD发生和发展的潜在联系，希望对进一步发现PD发病机理和防御机制有所帮助。
关键词： 葡萄糖脑苷脂酶; GBA; 戈谢病; 帕金森病; α-突触核蛋白
分类号：R338;Q42;R741

GBA mutations and Parkinson’s disease
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
Abstract
Parkinson’s disease(PD) is a common neurodegenerative disease characterized by thedegeneration of dopaminergic neuronsin the substantia nigra and the intraneuronal Lewy bodiesin 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 betweenGBAmutations 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 betweenGBAmutations and PD pathogenesis, which may show novel insights into PD etiology and therapeutics.
Key words: glucocerebrosidase; GBA; Gaucher disease; Parkinson’s disease; α-synuclein

收稿日期：2017-09-08　　录用日期：2018-01-02
通讯作者：宋宁　　E-mail: ningsong@qdu.edu.cn
DOI: 10.13294/j.aps.2018.0016
引用本文：
王冬霞, 谢俊霞, 宋宁. GBA突变与帕金森病的研究进展[J]. 生理学报 2018; 70 (3): 294-300.
WANG Dong-Xia, XIE Jun-Xia, SONG Ning. GBA mutations and Parkinson’s disease. Acta Physiol Sin 2018; 70 (3): 294-300 (in Chinese with English abstract).



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