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
  • 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.
PMID: 35732922 DOI: 10.1038/s41418-022-01027-7
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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