USP25 contributes to defective neurogenesis and cognitive impairments,The FASEB Journal

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USP25 contributes to defective neurogenesis and cognitive impairments
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-05-12 , DOI: 10.1096/fj.202300057r
Fang Cai _{1,

2} , Beibei Song ₂ , Yi Yang ₁ , Haikang Liao ₁ , Ran Li ₁ , Zhao Wang ₁ , Ruixue Cao ₁ , Huaqiu Chen ₃ , Juelu Wang ₂ , Yili Wu ₁ , Yun Zhang ₃ , Weihong Song _{1,

2,

3}

Affiliation

Both Down syndrome (DS) individuals and animal models exhibit hypo-cellularity in hippocampus and neocortex indicated by enhanced neuronal death and compromised neurogenesis. Ubiquitin-specific peptidase 25 (USP25), a human chromosome 21 (HSA21) gene, encodes for a deubiquitinating enzyme overexpressed in DS patients. Dysregulation of USP25 has been associated with Alzheimer's phenotypes in DS, but its role in defective neurogenesis in DS has not been defined. In this study, we found that USP25 upregulation impaired cell cycle regulation during embryonic neurogenesis and cortical development. Overexpression of USP25 in hippocampus promoted the neural stem cells to glial cell fates and suppressed neuronal cell fate by altering the balance between cyclin D1 and cyclin D2, thus reducing neurogenesis in the hippocampus. USP25-Tg mice showed increased anxiety/depression-like behaviors and learning and memory deficits. These results suggested that USP25 overexpression resulted in defective neurogenesis and cognitive impairments, which could contribute to the pathogenesis of DS. USP25 may be a potential pharmaceutical target for DS.

中文翻译：

USP25 导致有缺陷的神经发生和认知障碍

唐氏综合症 (DS) 个体和动物模型都表现出海马体和新皮质细胞减少，表现为神经元死亡增加和神经发生受损。泛素特异性肽酶 25 ( USP25)，人类 21 号染色体 (HSA21) 基因，编码在 DS 患者中过度表达的去泛素化酶。USP25 的失调与 DS 中的阿尔茨海默氏症表型有关，但其在 DS 中神经发生缺陷中的作用尚未明确。在这项研究中，我们发现 USP25 上调会损害胚胎神经发生和皮质发育过程中的细胞周期调节。USP25 在海马中的过表达通过改变细胞周期蛋白 D1 和细胞周期蛋白 D2 之间的平衡，促进神经干细胞向胶质细胞命运并抑制神经元细胞命运，从而减少海马中的神经发生。USP25-Tg 小鼠表现出焦虑/抑郁样行为增加以及学习和记忆缺陷。这些结果表明 USP25 过度表达导致神经发生缺陷和认知障碍，这可能有助于 DS 的发病机制。USP25 可能是 DS 的潜在药物靶点。

更新日期：2023-05-15

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