The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
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DOI：
10.1126/science.1232927
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发表时间：
2013-03-15
期刊：
影响因子：
56.9
通讯作者：
Edbauer, Dieter
中科院分区：
文献类型：
--
作者：
Mori, Kohji;Weng, Shih-Ming;Edbauer, Dieter
C9 orf 72编码区上游GGGGCC六核苷酸重复序列的扩增是家族性额颞叶变性和肌萎缩侧索硬化症（FTLD/ALS）的最常见原因，但涉及的病理机制尚不清楚。与其他FTLD/ALS变体一样，错误折叠蛋白的特征性细胞内包涵体定义了C9 orf 72病理学，但大多数包涵体的核心蛋白仍然未知。在这里，我们发现，大多数这些特征性的夹杂物含有聚-（Gly-Ala），并在较小程度上，聚-（Gly-Pro）和聚-（Gly-Arg）二肽重复蛋白，推测产生的非ATG启动翻译从扩大GGGGCC重复在三个阅读框架。这些发现直接将FTLD/ALS相关基因突变与C9 orf 72六核苷酸扩增患者的主要病理学联系起来。
Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.