Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease.
Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease.
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DOI：
10.1016/j.cmet.2013.04.014
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发表时间：
2013-06-04
期刊：
影响因子：
29
通讯作者：
Duchen MR
中科院分区：
文献类型：
--
作者：
Osellame LD;Rahim AA;Hargreaves IP;Gegg ME;Richard-Londt A;Brandner S;Waddington SN;Schapira AHV;Duchen MR
葡萄糖脑苷酶（gba）基因突变导致戈谢病（GD），最常见的溶酶体贮积症，并增加对帕金森病（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，但两者神经退行性变的细胞机制尚不清楚。通过小鼠神经性GD模型，我们发现缺乏gba的神经元和星形胶质细胞的自噬机制和蛋白酶体机制存在缺陷。神经变性标志物- p62/SQSTM1，泛素化蛋白和不溶性α-突触核蛋白积累。线粒体功能失调，碎片化，呼吸受损，呼吸链复合体活性降低，ATP合酶逆转维持电位下降。因此，由于自噬受损和蛋白酶体通路功能失调，原发性溶酶体缺陷导致功能失调线粒体的积累。这些数据为GD线粒体功能障碍提供了确凿的证据，并为PD和PD- gba的发病机制提供了见解。α-突触核蛋白在gba敲除小鼠的脑干神经元和星形胶质细胞中积累并形成沉积。gba敲除小鼠的神经元和星形胶质细胞中存在功能失调的线粒体，线粒体不募集Parkin并在gba敲除神经元中积累
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. Autophagic and proteasomal pathways are suppressed in gba knockout mice α-Synuclein accumulates and forms deposits in gba knockout mouse brainstem Neurons and astrocytes from gba knockout mice harbor dysfunctional mitochondria Mitochondria do not recruit Parkin and accumulate in gba knockout neurons
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影响因子：
--
作者：
Mitsui, Jun;Mizuta, Ikuko;Tsuji, Shoji
通讯作者：
Tsuji, Shoji
影响因子：
3.5
作者：
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影响因子：
56.9
作者：
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通讯作者：
Heutink, P
DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
Youle RJ
影响因子：
5.3
作者：
Abramov, AY;Canevari, L;Duchen, MR
通讯作者：
Duchen, MR