研究利用病毒策略通过综合应激反应逆转认知功能障碍，这一成果由贝勒医学院Mauro Costa-Mattioli团队经过不懈努力而取得。2026年4月2日出版的《科学》发表了这项成果。

研究小组通过研究与智力残疾相关的PPP1R15B^R658C基因变异来研究持续的ISR激活如何影响认知表现。为了模拟这种情况，该研究团队生成了一个插入致病等位基因的同源系。这种变异破坏了PPP1R15BPP1磷酸酶复合物，导管持续性ISR激活，蛋白合成受损和长期记忆缺陷。研究小组证明Ppp1r15b^R658C小鼠的认知和突触损伤直接由ISR激活引起。

此外，研究小组还鉴定了PPP1R15B的病毒同源物DP71L，它是一种有效的泛ISR抑制剂。DP71L在唐氏综合症、阿尔茨海默病和衰老的多主题模型中逆转了认知和突触缺陷，并增强了健康小鼠的突触可塑性和记忆。

据悉，综合应激反应（integrated stress response， ISR）对细胞稳态和认知功能至关重要。

附：英文原文

Title: Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response

Author: Lucas C. Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W. Dooling, Yuwei Liu, I-Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A. Debeaubien, Tristan Croll, D. John Lee, Christopher Arthur, Thomas E. Dever, Peter Walter, Jin Chen, Adam Frost, Mauro Costa-Mattioli

Issue&Volume: 2026-04-02

Abstract: The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15BPP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer’s disease, and aging, and enhanced synaptic plasticity and memory in healthy mice.

DOI: aea8782

Source: https://www.science.org/doi/10.1126/science.aea8782