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Luo R, Fan Y, Yang J, et al. A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline. Signal Transduct Target Ther. 2021;6(1):325doi: 10.1038/s41392-021-00748-4.
Luo, R., Fan, Y., Yang, J., Ye, M., Zhang, D. F., Guo, K., Li, X., Bi, R., Xu, M., Yang, L. X., Li, Y., Ran, X., Jiang, H. Y., Zhang, C., Tan, L., Sheng, N., & Yao, Y. G. (2021). A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline. Signal transduction and targeted therapy, 6(1), 325. https://doi.org/10.1038/s41392-021-00748-4
Luo, Rongcan, et al. "A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline." Signal transduction and targeted therapy vol. 6,1 (2021): 325. doi: https://doi.org/10.1038/s41392-021-00748-4
Luo R, Fan Y, Yang J, Ye M, Zhang DF, Guo K, Li X, Bi R, Xu M, Yang LX, Li Y, Ran X, Jiang HY, Zhang C, Tan L, Sheng N, Yao YG. A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline. Signal Transduct Target Ther. 2021 Aug 31;6(1):325. doi: 10.1038/s41392-021-00748-4. PMID: 34465723; PMCID: PMC8408221.
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Signal Transduct Target Ther. 2021 Aug 31;6(1):325. doi: 10.1038/s41392-021-00748-4.

A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline.

Signal transduction and targeted therapy

Rongcan Luo, Yu Fan, Jing Yang, Maosen Ye, Deng-Feng Zhang, Kun Guo, Xiao Li, Rui Bi, Min Xu, Lu-Xiu Yang, Yu Li, Xiaoqian Ran, Hong-Yan Jiang, Chen Zhang, Liwen Tan, Nengyin Sheng, Yong-Gang Yao

Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected].
  2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
  3. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
  4. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  5. Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
  6. Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  7. Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China.
  8. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China.
  9. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected].
  10. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected].
  11. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. [email protected].

PMID: 34465723 PMCID: PMC8408221 DOI: 10.1038/s41392-021-00748-4

Abstract

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP, PSEN1, and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

© 2021. The Author(s).

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