Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361005, China.
Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, Fujian, 350004, China.
Cell Death Differ. 2022 Dec;29(12):2417-2428. doi: 10.1038/s41418-022-01027-7. Epub 2022 Jun 22.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease featured with memory loss and cognitive function impairments. Chronic mitochondrial stress is a vital pathogenic factor for AD and finally leads to massive neuronal death. However, the underlying mechanism is unclear. By proteomic analysis, we identified a new mitochondrial protein, cell-cycle exit and neuronal differentiation 1 (CEND1), which was decreased significantly in the brain of 5xFAD mice. CEND1 is a neuronal specific protein and locates in the presynaptic mitochondria. Depletion of CEND1 leads to increased mitochondrial fission mediated by upregulation of dynamin related protein 1 (Drp1), resulting in abnormal mitochondrial functions. CEND1 deficiency leads to cognitive impairments in mice. Overexpression of CEND1 in the hippocampus of 5xFAD mice rescued cognitive deficits. Moreover, we identified that CDK5/p25 interacted with and phosphorylated CEND1 which promoted its degradation. Our study provides new mechanistic insights in mitochondrial function regulations by CEND1 in Alzheimer's disease.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是记忆力丧失和认知功能障碍。慢性线粒体应激是 AD 的一个重要致病因素，最终导致大量神经元死亡。然而，其潜在机制尚不清楚。通过蛋白质组学分析，我们鉴定出一种新的线粒体蛋白，细胞周期退出和神经元分化 1（CEND1），其在 5xFAD 小鼠的大脑中显著减少。CEND1 是一种神经元特异性蛋白，位于突触前线粒体中。CEND1 的耗竭导致通过上调动力相关蛋白 1（Drp1）介导的线粒体裂变增加，导致线粒体功能异常。CEND1 缺乏导致小鼠认知障碍。在 5xFAD 小鼠的海马体中过表达 CEND1 可挽救认知缺陷。此外，我们发现 CDK5/p25 与 CEND1 相互作用并使其磷酸化，从而促进其降解。我们的研究为阿尔茨海默病中线粒体功能调节的 CEND1 提供了新的机制见解。
