Nat Commun:CIB2调控mTORC1信号影响视觉功能

2021-06-29 xiaozeng MedSci原创

杆状和锥状光感受器(PR)是高度特化的神经元,是信号转导的场所,其能够将光照转换为眼睛中的神经元信号。

杆状和锥状光感受器(PR)是高度特化的神经元,是信号转导的场所,其能够将光照转换为眼睛中的神经元信号。

PR视细胞外节段(OS)专用于光转导,然而,其在很大程度上依赖于视网膜色素上皮细胞(RPE)的支持,RPE是一种单层极化的鹅卵石状的有丝分裂后细胞。


越来越多的证据表明,RPE的功能障碍,特别是在OS消化和清除方面,会导致与年龄相关的光感受器功能障碍,但并不会出现严重的视网膜变性。

年龄相关性黄斑变性(AMD)是一种多因素的神经退行性疾病,其是一种进行性黄斑变性疾病。AMD常导致中心视力丧失和不可逆性失明,影响10%的65-75岁人群以及25%的75岁以上人群。尽管目前相关的分子机制仍难以捉摸,但研究发现自噬缺陷与AMD的发生相关。


在该研究中,研究人员发现,在小鼠模型中CIB2(钙整合素结合蛋白2)的缺乏会导致与年龄相关的病变,包括视网膜下色素上皮细胞(RPE)的沉积、玻璃膜疣(drusen)标志物APOE、C3、Aβ和酯化胆固醇的显著积累以及视觉功能的受损,这些病变可通过外源性维甲酸来进行挽救。

CIB2缺失会导致年龄相关的光感受器功能障碍

Cib2突变小鼠模型表现出了溶酶体能力和自噬清除率的降低,并提高了mTORC1信号水平,这是自噬的负调节因子。研究人员在干性AMD患者的RPE/脉络膜组织中观察到了一致的分子缺陷。


机制研究显示,CIB2能够通过优先结合“空核苷酸”或非活性GDP负载的Rheb来负调节mTORC1信号通路。而上调的mTORC1信号与淋巴管平滑肌瘤(LAM)相关。进一步的研究发现,在LAM患者来源的成纤维细胞中过表达CIB2能够下调过度活跃的mTORC1信号。

Cib2突变小鼠模型模拟干性AMD

总而言之,该研究发现CIB2的调节作用对于治疗AMD和其他mTORC1相关疾病具有重要意义。


原始出处:

Sethna, S., Scott, P.A., Giese, A.P.J. et al. CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function. Nat Commun 12, 3906 (23 June 2021).

 

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    2022-04-10 liye789132251
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    2021-06-29 liuli5079
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    2021-06-30 雕雕
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    2021-06-30 zhouqu_8

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