The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models.
The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models.
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DOI：
10.3389/fnmol.2017.00196
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发表时间：
2017
影响因子：
4.8
通讯作者：
Yang SH
中科院分区：
文献类型：
--
作者：
Hsu JY;Jhang YL;Cheng PH;Chang YF;Mao SH;Yang HI;Lin CW;Chen CM;Yang SH
脊髓小脑性共济失调3型（SCA 3），又称Machado-Joseph病，是一种常染色体显性遗传疾病，由ATXN 3基因中多聚谷氨酰胺异常扩增引起，导致SCA 3患者神经退行性变。与其他神经退行性疾病类似，观察到线粒体功能障碍导致SCA 3患者的神经元死亡。基于先前的研究，发现突变体ATXN 3的蛋白水解切割在SCA 3模型中产生截短的C-末端片段。然而，这些截短的突变片段是否干扰线粒体功能并导致病理性死亡仍不清楚。在这里，我们使用神经母细胞瘤细胞和转基因小鼠模型来研究截短突变ATXN 3对线粒体功能的影响。在不同的模型中，我们观察到截短突变体ATXN 3加速聚集体的形成，这些聚集体易位到细胞核中形成核内聚集体。此外，截短突变体ATXN 3引起更多的线粒体分裂，并降低线粒体融合标志物，包括Mfn-1和Mfn-2的表达。此外，截短突变体ATXN 3降低线粒体膜电位，增加活性氧，最终增加细胞死亡率。在转基因小鼠模型中，截短的突变ATXN 3也导致小脑中更多的线粒体功能障碍、神经变性和细胞死亡。本研究支持SCA 3中的毒性片段假说，并提供了证据，截短突变体ATXN 3比全长突变体在体外和体内更好。
Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.