C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy.
C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy.
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DOI：
10.1080/21541248.2016.1212688
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发表时间：
2017-07-03
期刊：
影响因子：
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通讯作者：
Sellier, Chantal
中科院分区：
文献类型：
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作者：
Corbier, Camille;Sellier, Chantal
肌萎缩侧索硬化症和额颞叶痴呆（ALS-FTD）是一种毁灭性的神经退行性疾病，分别影响脊髓的运动神经元和额叶和颞叶皮层的神经元。ALS-FTD最常见的遗传原因是C9ORF72基因第一个内含子内GGGGCC重复序列的扩增。然而，对C9ORF72的功能知之甚少。最近，我们和其他人发现C9ORF72与SMCR8和WDR41蛋白形成稳定的复合物。该复合物作为GDP/GTP交换因子，用于小RAB GTP酶Rab8a和Rab39b。由于Rab8和Rab39参与了巨噬，我们测试了C9ORF72在这一机制中的作用。神经元培养物中C9ORF72表达降低导致以p62/SQSTM1聚集物积累为特征的自噬功能障碍。然而，C9ORF72表达的缺失并不会导致主要的神经元细胞死亡，这表明可能需要第二次应激来促进细胞毒性。Ataxin-2 （ATXN2）中大小的聚谷氨酰胺重复序列是ALS-FTD的重要遗传修饰因子。我们发现，C9ORF72表达的降低与ATXN2的毒性和聚集与中等大小的聚谷氨酰胺（30Q）协同作用。总的来说，我们的数据表明，C9ORF72的表达减少导致次优自噬，使神经元对第二次应激敏感。这些数据表明，C9ORF72的表达降低可能在一定程度上参与了ALS-FTD的发病机制。
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) are devastating neurodegenerative disease affecting motoneurons from the spinal chord and neurons from the frontal and temporal cortex, respectively. The most common genetic cause for ALS-FTD is an expansion of GGGGCC repeats within the first intron of the C9ORF72 gene. However, little is known on the function of C9ORF72. Recently, other and we found that C9ORF72 forms a stable complex with the SMCR8 and WDR41 proteins. This complex acts as a GDP/GTP exchange factor for the small RAB GTPases Rab8a and Rab39b. Since Rab8 and Rab39 are involved in macroautophagy, we tested the role of C9ORF72 in this mechanism. Decrease expression of C9ORF72 in neuronal cultures leads to autophagy dysfunction characterized by accumulation of aggregates of p62/SQSTM1. However, loss of C9ORF72 expression does not cause major neuronal cell death, suggesting that a second stress may be required to promote cell toxicity. Intermediate size of polyglutamine repeats within Ataxin-2 (ATXN2) is an important genetic modifier of ALS-FTD. We found that decrease expression of C9ORF72 synergizes the toxicity and aggregation of ATXN2 with intermediate size of polyglutamine (30Q). Overall, our data suggest that reduce expression of C9ORF72 causes suboptimal autophagy that sensitizes neurons to a second stress. These data suggest that reduce expression of C9ORF72 may partly contribute to ALS-FTD pathogenesis.