Modulation of β-glucocerebrosidase increases α-synuclein secretion and exosome release in mouse models of Parkinson's disease
Modulation of β-glucocerebrosidase increases α-synuclein secretion and exosome release in mouse models of Parkinson's disease
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DOI：
10.1093/hmg/ddy075
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发表时间：
2018-05-15
影响因子：
3.5
通讯作者：
Vekrellis, Kostas
中科院分区：
文献类型：
--
作者：
Papadopoulos, Vassilis E.;Nikolopoulou, Georgia;Vekrellis, Kostas
葡萄糖脑苷脂酶基因（GBA）突变是帕金森病（PD）最常见的遗传因素，并且与PD中葡萄糖脑苷脂酶（GCase）酶活性降低相关。没有GBA突变的PD患者在中枢神经系统中也表现出较低水平的GCase活性，这表明酶活性在疾病发病机制中的潜在贡献，可能是通过改变溶酶体功能。α-突触核蛋白（ASYN），一种在PD发病机制中具有核心作用的蛋白质，已显示部分与外来体相关地分泌。通过GCase的内吞途径的功能障碍可能导致ASYN的外泌体释放改变。本研究的目的是检查在体内和体外操纵GCase活性是否会影响ASYN的积累和分泌。GCase在体外过表达导致外泌体分泌的显著减少。通过在A53 T-突触核蛋白α基因Tg小鼠中施用共价抑制剂conduritol-B环氧化物，体内GCase活性的慢性抑制显著升高了细胞内寡聚ASYN种类。重要的是，GCase抑制诱导释放的脑外泌体以及外泌体相关ASYN寡聚体的数量显著增加。最后，病毒介导的突变GBA在小鼠纹状体中的表达增加了同一区域的ASYN分泌。总之，这些结果首次提供了证据表明，在慢性体内环境中GCase的减少或突变GCase的过表达可以影响ASYN的分泌。这种作用可能介导ASYN的增强传播，从而驱动GBA相关PD的病理学。
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's disease (PD) and are associated with decreased glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. alpha-synuclein (ASYN), a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes. It is possible that a dysfunction of the endocytic pathway through GCase may result in altered exosome release of ASYN. The aim of this study was to examine whether manipulating GCase activity in vivo and in vitro could affect ASYN accumulation and secretion. GCase overexpression in vitro resulted in a significant decrease of exosome secretion. Chronic inhibition of GCase activity in vivo, by administration of the covalent inhibitor conduritol-B epoxide in A53T-synuclein alpha gene Tg mice significantly elevated intracellular oligomeric ASYN species. Importantly, GCase inhibition, induced a profound increase in the number of brain exosomes released, as well as exosome-associated ASYN oligomers. Finally, virus-mediated expression of mutant GBA in the mouse striatum increased ASYN secretion in the same region. Together, these results provide for the first time evidence that a decrease of GCase or overexpression of mutant GCase in a chronic in vivo setting can affect ASYN secretion. Such effects may mediate enhanced propagation of ASYN, driving pathology in GBA-associated PD.