Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

神经退行性疾病是由进行性神经元丢失引起的，目前还没有完整的治疗方法。神经炎症是神经退行性疾病的共同特征，并与神经退行性病变的进展有关。小胶质细胞的失调激活会导致神经炎症，并已被强调为治疗策略中的治疗目标。在这里，我们确定了新的治疗候选 ALGERNON2（改变神经元 2 的生成）并证明 ALGERNON2 抑制促炎细胞因子的产生并挽救 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 中的神经退行性变——诱发帕金森病模型。ALGENON2 稳定 cyclinD1/p21 复合物，导致核因子红细胞 2 相关因子 2 (Nrf2) 的上调，这有助于抗氧化和抗炎反应。值得注意的是，ALGERNON2 增强了其他神经炎症条件下的神经元存活率，例如将诱导的多能干细胞衍生的多巴胺能神经元移植到鼠脑中。总之，我们提出 p21-Nrf2 通路的小胶质细胞增强可以促进神经元存活，并为神经炎症触发的神经变性提供新的治疗潜力。