1Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Research; University College London; London, UK.
Autophagy. 2013 Oct;9(10):1633-5. doi: 10.4161/auto.25878. Epub 2013 Aug 13.
Mutations in the GBA gene encoding glucocerebrosidase cause Gaucher disease (GD), the most prevalent of the lysosomal storage disorders (LSDs) and increase susceptibility to Parkinson disease (PD). Clinically the two disorders can present in a similar manner with analogous pathological features, suggesting mechanistic links between the two disease states. An increasing body of evidence implicates defects in quality control pathways in both, and suggests that LSDs, as a group, can be classed as disorders of autophagy. Using a mouse model of type II neuronopathic GD, we observed global defects in cellular quality control pathways in midbrain neurons and astrocytes. Our data suggest that downregulation of autophagy, mitophagy, and the ubiquitin-proteasome system (UPS) results in accumulation of dysfunctional and fragmented mitochondria, insoluble SNCA/α-synuclein deposits and ubiquitinated proteins. These observations show that dysfunction of cellular quality control pathways lead to impaired energy and free radical homeostasis, providing new insights into the mechanisms of neurodegeneration in GD and illuminating the links between GD and PD.
GBA 基因突变导致葡萄糖脑苷脂酶缺乏症（Gaucher disease，GD），这是溶酶体贮积症（lysosomal storage disorders，LSDs）中最常见的一种，并且增加了帕金森病（Parkinson disease，PD）的易感性。在临床上，这两种疾病的表现方式相似，具有类似的病理特征，提示这两种疾病状态之间存在机制联系。越来越多的证据表明，两种疾病的质量控制途径都存在缺陷，并表明溶酶体贮积症作为一组疾病，可以归类为自噬障碍。我们使用 II 型神经元神经病变 GD 的小鼠模型，观察到中脑神经元和星形胶质细胞中细胞质量控制途径的全局缺陷。我们的数据表明，自噬、线粒体自噬和泛素蛋白酶体系统（ubiquitin-proteasome system，UPS）的下调导致功能失调和碎片化的线粒体、不溶性 SNCA/α-突触核蛋白沉积物和泛素化蛋白的积累。这些观察结果表明，细胞质量控制途径的功能障碍导致能量和自由基平衡受损，为 GD 中的神经退行性变机制提供了新的见解，并阐明了 GD 和 PD 之间的联系。
