Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease
Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease
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DOI：
10.1007/s40263-020-00746-0
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发表时间：
2020-07-01
期刊：
影响因子：
6
通讯作者：
Schapira, Anthony H., V
中科院分区：
文献类型：
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作者：
Menozzi, Elisa;Schapira, Anthony H., V
葡萄糖脑苷脂酶（GBA 1）基因突变是帕金森病（PD）最常见的遗传风险因素。GBA 1纯合子或复合杂合子突变可引起以葡萄糖脑苷脂酶（GCase）活性缺陷为特征的溶酶体贮积症戈谢病（GD）。与非携带者相比，GD I型和GBA 1致病性变体杂合携带者发生PD的风险增加约10至20倍。在没有GBA 1突变的PD患者中，GCase活性也降低，表明GCase溶酶体途径可能参与PD发病机制。现有证据表明，GCase可以以不同的方式影响α-突触核蛋白病理学。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运输。此外，缺乏GCase导致底物的积累，所述底物继而可以结合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。旨在增强GCase活性、通过小分子伴侣增加错误折叠的GCase蛋白的运输或减少底物积累的靶向疗法已在临床前和临床试验中进行了测试。本文综述了GCase与α-突触核蛋白的分子机制，并讨论了通过靶向GCase通路影响PD进展的治疗药物。
Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygousGBA1mutations 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 ofGBA1have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients withoutGBA1mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect alpha-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 alpha-synuclein and promote pathological formation of aggregates. Furthermore, alpha-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and alpha-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 alpha-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.