1. Academic Validation
  2. CEND1 deficiency induces mitochondrial dysfunction and cognitive impairment in Alzheimer's disease

CEND1 deficiency induces mitochondrial dysfunction and cognitive impairment in Alzheimer's disease

  • Cell Death Differ. 2022 Jun 22. doi: 10.1038/s41418-022-01027-7.
Wenting Xie  # 1 Dong Guo  # 1 Jieyin Li  # 1 Lei Yue 2 Qi Kang 1 Guimiao Chen 1 Tingwen Zhou 1 Han Wang 1 Kai Zhuang 1 Lige Leng 1 Huifang Li 1 Zhenyi Chen 3 Weiwei Gao 4 Jie Zhang 5 6 7
Affiliations

Affiliations

  • 1 Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361005, China.
  • 2 Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, Fujian, 350004, China.
  • 3 Department of Anesthesiology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361005, China.
  • 4 Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, Fujian, 350004, China. [email protected].
  • 5 Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361005, China. [email protected].
  • 6 Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, Fujian, 350004, China. [email protected].
  • 7 Department of Anesthesiology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361005, China. [email protected].
  • # Contributed equally.
Abstract

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.

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