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首页> 外文期刊>Proceeding of the Singapore National Academy of Science >WWOX is a Risk Factor for Alzheimer's Disease: How and Why?
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WWOX is a Risk Factor for Alzheimer's Disease: How and Why?

机译：WWOX阿尔茨海默病的危险因素:如何做,为什么?

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摘要

A recent large genome-wide association meta-analysis revealed that the human WWOX gene is regarded as one of the five newly identified risk factors for Alzheimer's disease (AD). However, this study did not functionally characterize how WWOX protein deficiency affects AD initiation, progression and neurodegeneration. In this review, evidence and perspectives are provided regarding how WWOX works in limiting neurodegeneration. Firstly, loss of WWOX/ Wwox gene leads to severe neural diseases with degeneration, metabolic disorder and early death in the newborns. Downregulation of pY33-WWOX may start at middle ages, and this leads to slow aggregation of a cascade of proteins, namely TRAPPC6AΔ,TIAF1 and SH3GLB2, that leads to amyloid-beta (Aβ) formation and tau tangle formation in old-aged AD patients. Secondly, functional antagonism between tumor suppressors p53 and WWOX may occur in vivo, in which p53-mediated inflammation is blocked by WWOX. Loss of balance in the functional antagonism leads to aggregation of pathogenic proteins for AD such as tau and Aβ in the brain cortex and hippocampus. Thirdly, downregulation of pY33-WWOX is accompanied by upregulation of pS14-WWOX. The event frequently correlates with enhanced AD progression and cancer cell growth in vivo. A small peptide Zfra4-10 dramatically suppresses pS14-WWOX and restores memory loss in triple transgenic (3xTg) mice, and inhibits cancer growth in mice as well. Finally, a supporting scenario is that WWOX deficiency induces enhanced cell migration and loss of cell-to-cell recognition. This allows the generation of neuronal heterotopia and associated epileptic seizure in WWOX-deficient newborn patients.
机译：最近的全基因组关联荟萃分析显示,人类WWOX基因被认为是一个五新发现吗阿尔茨海默病(AD)的危险因素。然而,这项研究没有功能WWOX蛋白缺乏症如何影响的特点广告开始,进展和退化。综述、证据和观点提供关于如何WWOX在限制工作神经退化。基因会导致严重的神经疾病变性、代谢紊乱和过早死亡在新生儿。在中世纪开始,这导致缓慢聚合级联的蛋白质,即TRAPPC6AΔ,TIAF1 SH3GLB2,导致淀粉样β蛋白(β)形成和τ纠结形成在AD患者一根一根的拔掉。功能之间的对抗肿瘤的抑制p53和WWOX体内可能发生,被WWOX p53-mediated炎症。失去平衡功能对立导致致病蛋白的聚合广告如τ和大脑皮层和β海马体。伴随着upregulation pS14-WWOX。事件通常与增强广告进展和体内癌细胞的生长。小肽Zfra4-10显著抑制pS14-WWOX和恢复记忆丧失的三倍转基因小鼠(3 xtg),抑制癌症老鼠的增长。情况是,WWOX缺乏诱导增强细胞迁移以及细胞间的损失识别。神经异位和相关癫痫WWOX-deficient新生儿患者的发作。

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