Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, United States of America.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, United States of America.
Pharmacol Ther. 2023 Jun;246:108419. doi: 10.1016/j.pharmthera.2023.108419. Epub 2023 Apr 19.
The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk. Patients with PD carrying GBA1 variants show a more rapidly progressive phenotype compared to non-carriers, emphasising the need for disease modifying treatments targeting the GBA1 pathway. Several mechanisms secondary to GCase dysfunction are potentially responsible for the pathological changes leading to PD. Misfolded GCase proteins induce endoplasmic reticulum stress and subsequent unfolded protein response and impair the autophagy-lysosomal pathway. This results in α-synuclein accumulation and spread, and promotes neurodegenerative changes. Preclinical evidence also shows that products of GCase activity can promote accumulation of α-synuclein, however there is no convincing evidence of substrate accumulation in GBA1-PD brains. Altered lipid homeostasis secondary to loss of GCase activity could also contribute to PD pathology. Treatments that target the GBA1 pathway could reverse these pathological processes and halt/slow the progression of PD. These range from augmentation of GCase activity via GBA1 gene therapy, restoration of normal intracellular GCase trafficking via molecular chaperones, and substrate reduction therapy. This review discusses the pathways associated with GBA1-PD and related novel GBA1-targeted interventions for PD treatment.
GBA1 基因编码溶酶体酶葡萄糖脑苷脂酶（GCase），该酶参与鞘脂代谢。GBA1 的双等位基因变异会导致戈谢病（Gaucher disease，GD），这是一种溶酶体贮积症，其特征是 GCase 活性丧失和 GCase 底物异常细胞内积累。GBA1 变异携带者患帕金森病（Parkinson disease，PD）的风险增加，根据变异严重程度，比值比范围为 2.2 至 30。杂合状态下不引起 GD 的 GBA1 变异也可以增加 PD 风险。与非携带者相比，携带 GBA1 变异的 PD 患者表现出更快速进展的表型，这强调了针对 GBA1 途径的疾病修饰治疗的必要性。GCase 功能障碍的几种机制可能导致导致 PD 的病理变化。错误折叠的 GCase 蛋白诱导内质网应激和随后的未折叠蛋白反应，并损害自噬溶酶体途径。这导致α-突触核蛋白的积累和扩散，并促进神经退行性变化。临床前证据还表明，GCase 活性产物可以促进α-突触核蛋白的积累，但是在 GBA1-PD 大脑中没有令人信服的底物积累证据。GCase 活性丧失引起的脂质动态平衡改变也可能导致 PD 病理学。靶向 GBA1 途径的治疗方法可以逆转这些病理过程并阻止/减缓 PD 的进展。这些方法包括通过 GBA1 基因治疗增加 GCase 活性、通过分子伴侣恢复正常的细胞内 GCase 运输以及底物减少治疗。这篇综述讨论了与 GBA1-PD 相关的途径以及用于治疗 PD 的相关新型 GBA1 靶向干预措施。
