Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5-mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2-ERK1/2 interactions.

中文翻译：

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核 ERK1/2 信号增强通过 Importinα1/KPNA2 增强神经保护和认知

细胞信号传导是神经元活动的核心，其失调可能导致神经退行性和认知能力下降。在这里，我们发现神经元 ERK 信号传导的选择性遗传增强可防止小鼠大脑体外和体内的细胞死亡，而 ERK 信号传导的减弱则相反。这种由增强的核 ERK 活性介导的神经保护作用也可以由新型细胞穿透肽 RB5 诱导。体外施用 RB5 会破坏 ERK1 MAP 激酶与 importinα1/KPNA2（而非 ERK2）的优先相互作用，促进 ERK1/2 核转位，并增强整体 ERK 活性。重要的是，RB5体内治疗可促进亨廷顿病 (HD)、阿尔茨海默病 (AD) 和帕金森病 (PD) 小鼠模型的神经保护，并增强 HD 人类细胞模型中的 ERK 信号传导。此外，RB5 介导的 ERK 核信号传导增强可促进突触可塑性，增强健康啮齿动物的认知能力，并挽救 AD 和 HD 模型中的认知障碍。报道的多种神经退行性疾病共有的分子机制揭示了一种基于 KPNA2-ERK1/2 相互作用调节的潜在新治疗靶点方法。