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首页> 外文期刊>Cell metabolism >Mitochondria and quality control defects in a mouse model of gaucher disease - Links to parkinson's disease
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Mitochondria and quality control defects in a mouse model of gaucher disease - Links to parkinson's disease

机译：高雪氏病小鼠模型中的线粒体和质量控制缺陷-帕金森氏病的链接

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摘要

Mutations in the glucocerebrosidase (gba) gene cause Gaucher disease (GD), the most common lysosomal storage disorder, and increase susceptibility to Parkinson's disease (PD). While the clinical and pathological features of idiopathic PD and PD related to gba (PD-GBA) mutations are very similar, cellular mechanisms underlying neurodegeneration in each are unclear. Using a mouse model of neuronopathic GD, we show that autophagic machinery and proteasomal machinery are defective in neurons and astrocytes lacking gba. Markers of neurodegeneration - p62/SQSTM1, ubiquitinated proteins, and insoluble α-synuclein - accumulate. Mitochondria were dysfunctional and fragmented, with impaired respiration, reduced respiratory chain complex activities, and a decreased potential maintained by reversal of the ATP synthase. Thus a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways. These data provide conclusive evidence for mitochondrial dysfunction in GD and provide insight into the pathogenesis of PD and PD-GBA.
机译：葡萄糖脑苷脂酶（gba）基因的突变会引起高雪氏病（GD），这是最常见的溶酶体贮积病，并增加了对帕金森氏病（PD）的易感性。虽然特发性PD和与gba（PD-GBA）突变相关的PD的临床和病理特征非常相似，但尚不清楚每种神经变性的细胞机制。使用神经病性GD的小鼠模型，我们显示自噬机制和蛋白酶体机制在缺乏gba的神经元和星形胶质细胞中有缺陷。神经变性的标志物-p62 / SQSTM1，泛素化蛋白和不溶性α-突触核蛋白-会累积。线粒体功能紊乱和支离破碎，呼吸功能受损，呼吸链复合物活性降低，ATP合酶逆转维持的潜力降低。因此，原发性溶酶体缺陷是由于自噬功能障碍和蛋白酶体途径异常导致线粒体功能障碍的积累。这些数据为GD中的线粒体功能障碍提供了确凿的证据，并为PD和PD-GBA的发病机理提供了见识。

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