Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Biophys Chem. 2021 Jun;273:106534. doi: 10.1016/j.bpc.2020.106534. Epub 2020 Dec 25.
Mutations in the gene GBA, encoding glucocerebrosidase (GCase), are the highest genetic risk factor for Parkinson's disease (PD). GCase is a lysosomal glycoprotein responsible for the hydrolysis of glucosylceramide into glucose and ceramide. Mutations in GBA cause a decrease in GCase activity, stability and protein levels which in turn lead to the accumulation of GCase lipid substrates as well as α-synuclein (αS) in vitro and in vivo. αS is the main constituent of Lewy bodies found in the brain of PD patients and an increase in its levels was found to be associated with a decrease in GCase activity/protein levels in vitro and in vivo. In this review, we describe the reported biophysical and biochemical changes that GBA mutations can induce in GCase activity and stability as well as the current overview of the levels of GCase protein/activity, αS and lipids measured in patient-derived samples including post-mortem brains, stem cell-derived neurons, cerebrospinal fluid, blood and fibroblasts as well as in SH-SY5Y cells. In particular, we report how the levels of αS and lipids are affected by/correlated to significant changes in GCase activity/protein levels and which cellular pathways are activated or disrupted by these changes in each model. Finally, we review the current strategies used to revert the changes in the levels of GCase activity/protein, αS and lipids in the context of PD.
基因突变 GBA，编码葡萄糖脑苷脂酶（GCase），是帕金森病（PD）的最高遗传风险因素。GCase 是一种溶酶体糖蛋白，负责将葡萄糖脑苷脂水解为葡萄糖和神经酰胺。GBA 突变导致 GCase 活性、稳定性和蛋白水平降低，进而导致 GCase 脂质底物以及α-突触核蛋白（αS）在体外和体内积累。αS 是 PD 患者大脑中Lewy 体的主要成分，其水平的增加与体外和体内 GCase 活性/蛋白水平的降低有关。在这篇综述中，我们描述了 GBA 突变可诱导 GCase 活性和稳定性的已知生物物理和生化变化，以及目前在患者来源样本中测量的 GCase 蛋白/活性、αS 和脂质水平的概述，包括死后大脑、干细胞衍生神经元、脑脊液、血液和成纤维细胞以及 SH-SY5Y 细胞。特别是，我们报告了αS 和脂质的水平如何受到 GCase 活性/蛋白水平显著变化的影响/相关，以及这些变化在每种模型中激活或破坏了哪些细胞途径。最后，我们综述了目前用于逆转 PD 背景下 GCase 活性/蛋白、αS 和脂质水平变化的策略。
