Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models.
Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models.
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DOI：
10.1038/srep31380
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发表时间：
2016-08-19
影响因子：
4.6
通讯作者：
Schapira AH
中科院分区：
文献类型：
--
作者：
Sanchez-Martinez A;Beavan M;Gegg ME;Chau KY;Whitworth AJ;Schapira AH
GBA基因突变是帕金森病（PD）的最大病因。GBA编码溶酶体葡萄糖脑苷酶（GCase），但GCase缺失导致PD的机制尚不清楚。自噬的抑制和内质网（ER）应激的产生都有牵连。突变的GCase可以在内质网中展开，并通过未展开的蛋白反应被降解，激活内质网应激并减少溶酶体GCase。通过血脑屏障的小分子伴侣帮助突变的GCase重新折叠并正确地运输到溶酶体是PD的推定治疗方法。我们用分子伴侣氨溴索和异马戈胺治疗带有杂合GBA突变的PD患者和表达人类野生型、N370S和L444P GBA的果蝇的成纤维细胞。在对照和突变的GBA成纤维细胞中，这两种伴侣蛋白都增加了GCase的水平和活性，但也增加了GBA mRNA的表达。果蝇中突变GBA的表达导致多巴胺能神经元丢失、进行性运动缺陷、内质网异常聚集和内质网应激报告基因Xbp1-EGFP水平升高。用这两种伴侣治疗可以降低内质网应激，防止运动功能的丧失，这为小分子伴侣在体内逆转突变的gba介导的内质网应激提供了原理证明，并可能被证明对治疗PD有效。
GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD. We treated fibroblast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomine. Both chaperones increased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts. Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss, a progressive locomotor defect, abnormal aggregates in the ER and increased levels of the ER stress reporter Xbp1-EGFP. Treatment with both chaperones lowered ER stress and prevented the loss of motor function, providing proof of principle that small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective for treating PD.