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细胞自噬基因异常可导致认知障碍

近日,日本横滨市立大学、东京大学等机构研究人员确定了一种与细胞自噬作用相关的基因,这种基因若出现异常,会导致阿尔茨海默氏症和帕金森氏症等神经变性疾病。相关研究发表在近期出版的《自然·遗传学》网络版上。

自噬是细胞吞噬自身细胞质蛋白或细胞器的过程,细胞借此分解无用蛋白,实现细胞自身的代谢需要和某些细胞器的更新。

这种罕见脑病被称作“伴随成人期神经退行性变性的儿童期静态脑病”(SENDA),患者大脑萎缩并伴随认知障碍。研究人员对确诊为SENDA的5名患者的基因进行了分析,发现这5名患者的WDR45基因都出现了变异。

研究发现,WDR45基因编码合成与自噬作用相关的蛋白质,而5名患者细胞中的WDR45基因变异后功能降低,使自噬作用出现异常,有可能由此最终导致了认知障碍。

此次研究成果显示,自噬作用的异常有可能导致认知障碍,这将有助于开发以自噬作用为基础的治疗方法。

了解更多:

De novo mutations in the autophagy geneWDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood

Nature Genetics, 24 February 2013 | doi:10.1038/ng.2562

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.

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