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Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease.
CNS Drugs ( IF 6 ) Pub Date : 2020-07-01 , DOI: 10.1007/s40263-020-00746-0
Elisa Menozzi 1 , Anthony H V Schapira 1
Affiliation  

Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD), characterized by deficient activity of the glucocerebrosidase enzyme (GCase). Both individuals with GD type I and heterozygous carriers of pathogenic variants of GBA1 have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients without GBA1 mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect α-synuclein pathology in different ways. Misfolded GCase proteins are retained in the endoplasmic reticulum, altering the lysosomal trafficking of the enzyme and disrupting protein trafficking. Also, deficient GCase leads to accumulation of substrates that in turn may bind α-synuclein and promote pathological formation of aggregates. Furthermore, α-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and α-synuclein. Targeted therapies aimed at enhancing GCase activity, augmenting the trafficking of misfolded GCase proteins by small molecule chaperones, or reducing substrate accumulation, have been tested in preclinical and clinical trials. This article reviews the molecular mechanisms linking GCase to α-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.



中文翻译:

增强葡萄糖脑苷脂酶的活性作为帕金森病的治疗方法。

葡糖脑苷脂酶 ( GBA1 ) 基因突变是帕金森病 (PD) 最常见的遗传风险因素。纯合或复合杂合GBA1突变导致溶酶体贮积症戈谢病 (GD),其特征是葡萄糖脑苷脂酶 (GCase) 的活性不足。与非携带者相比,GD I 型患者和GBA1致病变异杂合子携带者发生 PD 的风险增加约 10 至 20 倍。没有GBA1 的PD 患者的 GCase 活性也降低突变,表明 GCase 溶酶体途径可能参与 PD 发病机制。现有证据表明 GCase 可以以不同方式影响 α-突触核蛋白病理。错误折叠的 GCase 蛋白保留在内质网中,改变酶的溶酶体运输并破坏蛋白质运输。此外,缺乏 GCase 会导致底物积累,这些底物反过来可能会结合 α-突触核蛋白并促进聚集体的病理形成。此外,α-突触核蛋白本身可以降低GCase的酶活性,表明GCase和α-突触核蛋白之间存在双向相互作用。靶向治疗旨在增强 GCase 活性,通过小分子伴侣增加错误折叠 GCase 蛋白的运输,或减少底物积累,已经在临床前和临床试验中进行了测试。本文回顾了将 GCase 与 α-突触核蛋白联系起来的分子机制,并讨论了通过靶向 GCase 途径可以影响 PD 进展的治疗药物。

更新日期:2020-07-01
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