Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments
Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments
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DOI：
10.1016/j.nbd.2022.105663
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发表时间：
2022-02-19
影响因子：
6.1
通讯作者：
Schapira, Anthony H. V.
中科院分区：
文献类型：
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作者：
Gegg, Matthew E.;Menozzi, Elisa;Schapira, Anthony H. V.
内溶酶体系统功能障碍与散发性和家族性帕金森病（PD）的发病机制有关。据估计，编码溶酶体蛋白的基因变异与一半以上的PD病例有关。帕金森病最常见的遗传危险因素是GBA基因的变异，该基因编码溶酶体酶葡萄糖脑苷酶（GCase），参与鞘脂代谢。在这篇综述中，我们将描述GBA- pd的临床症状和病理，以及GBA变异类型如何影响这些症状和病理。随后将讨论神经元和胶质细胞中GCase缺乏可能导致PD发病的推测机制，特别强调α -突触核蛋白聚集体的积累和致病性α -突触核蛋白物种在细胞类型之间的传播。本文综述了神经鞘脂、磷脂和胆固醇在α -突触核蛋白错误折叠中的失调，以及神经炎症和GCase与LRRK2蛋白的相互作用，LRRK2蛋白是PD发病的另一个重要因素。对无表现的GBA携带者和GBA-PD队列的研究为确定PD进展的可靠生物标志物以及潜在治疗的临床试验提供了机会。本综述的最后一部分将描述提高GCase活性或减少毒性底物积累的临床前研究和临床试验。
Dysfunction of the endolysosomal system is implicated in the pathogenesis of both sporadic and familial Parkinson disease (PD). Variants in genes encoding lysosomal proteins have been estimated to be associated with more than half of PD cases. The most common genetic risk factor for PD are variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. In this review we will describe the clinical symptoms and pathology of GBA-PD, and how this might be affected by the type of GBA variant. The putative mechanisms by which GCase deficiency in neurons and glia might contribute to PD pathogenesis will then be discussed, with particular emphasis on the accumulation of alpha-synuclein aggregates and the spread of pathogenic alpha-synuclein species between the cell types. The dysregulation of not only sphingolipids, but also phospholipids and cholesterol in the misfolding of alpha-synuclein is reviewed, as are neuroinflammation and the interaction of GCase with LRRK2 protein, another important contributor to PD pathogenesis. Study of both non-manifesting GBA carriers and GBA-PD cohorts provides an opportunity to identify robust biomarkers for PD progression as well as clinical trials for potential treatments. The final part of this review will describe preclinical studies and clinical trials for increasing GCase activity or reducing toxic substrate accumulation.