Mitochondrial dysfunction associated with glucocerebrosidase deficiency.
Mitochondrial dysfunction associated with glucocerebrosidase deficiency.
复制标题
DOI：
10.1016/j.nbd.2015.09.006
复制
发表时间：
2016-06
影响因子：
6.1
通讯作者：
Schapira AH
中科院分区：
文献类型：
--
作者：
Gegg ME;Schapira AH
溶酶体水解酶葡萄糖脑苷脂酶 (GCase) 由 GBA 基因编码。 GBA 纯合突变会导致戈谢病 (GD)，一种溶酶体贮积症。此外，纯合子和杂合子 GBA 突变在数量上是罹患帕金森病 (PD) 的最大遗传风险因素，帕金森病是第二常见的神经退行性疾病。 GCase 活性的丧失会导致自噬溶酶体途径 (ALP) 受损，而自噬溶酶体途径是大分子降解和受损细胞器所必需的。 ALP 对 α-突触核蛋白的异常蛋白质处理发生在 GD 和 PD 中。 α-突触核蛋白是路易体的主要成分，路易体是 PD 的一个定义标志。在 GD 和 PD 中也观察到线粒体功能障碍。在这篇综述中，我们将描述 GCase 活性丧失后线粒体如何受到影响。还将讨论导致线粒体功能障碍的致病机制，重点关注 ALP（也称为线粒体自噬）可能抑制线粒体降解。与 GBA 突变相关的其他致病细胞过程（例如内质网中 GCase 的展开、钙失调和神经炎症）也将被描述。 ALP 受损和线粒体功能障碍是 GD 和 PD 之间常见的致病主题，这可能解释了为什么 GBA 突变会增加患 PD 的风险，而 PD 与散发性疾病非常相似。
The lysosomal hydrolase glucocerebrosidase (GCase) is encoded for by the GBA gene. Homozygous GBA mutations cause Gaucher disease (GD), a lysosomal storage disorder. Furthermore, homozygous and heterozygous GBA mutations are numerically the greatest genetic risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. The loss of GCase activity results in impairment of the autophagy‐lysosome pathway (ALP), which is required for the degradation of macromolecules and damaged organelles. Aberrant protein handling of α-synuclein by the ALP occurs in both GD and PD. α-synuclein is the principle component of Lewy bodies, a defining hallmark of PD. Mitochondrial dysfunction is also observed in both GD and PD. In this review we will describe how mitochondria are affected following loss of GCase activity. The pathogenic mechanisms leading to mitochondria dysfunction will also be discussed, focusing on the likely inhibition of the degradation of mitochondria by the ALP, also termed mitophagy. Other pathogenic cellular processes associated with GBA mutations that might contribute, such as the unfolding of GCase in the endoplasmic reticulum, calcium dysregulation and neuroinflammation will also be described. Impairment of the ALP and mitochondria dysfunction are common pathogenic themes between GD and PD and probably explain why GBA mutations increase the risk of developing PD that is very similar to sporadic forms of the disease.