A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-beta pathology and cognitive decline
机构：[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[2]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China[3]State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China[4]Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, China内科科室精神科昆明医科大学附属第一医院[5]Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China[6]Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China[7]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China[8]CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-beta (A beta) 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 A beta 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.
基金：
The study was
supported by the National Natural Science Foundation of China (31730037 to Y.-G.Y.,
31900737 to R.L., 82022017 to D.-F.Z.), the Strategic Priority Research Program (B) of
CAS (XDB02020003 to Y.-G.Y.), the Bureau of Frontier Sciences and Education, CAS
(grant no. QYZDJ-SSW-SMC005 to Y.-G.Y.), the Original Innovation Project “from 0 to 1”
of Basic Frontier Scientific Research Program, CAS (ZDBS-LY-SM031 to R.L.), the Yunnan
Science and Technology Plan Project (202001AT070107 to R.L.), the CAS “Light of West
China” Program (2020000023 to R.L.), the Youth Innovation Promotion Association of
CAS (to R.L. and D.-F.Z.), and the Training of High-Level Health Technical Personnel in
Yunnan Province, Medical Academic Leader (D-2018047 to H.-Y.J.).
第一作者机构：[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
共同第一作者：
通讯作者：
通讯机构：[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[2]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China[8]CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
推荐引用方式(GB/T 7714)：
Rongcan Luo,Yu Fan,Jing Yang,et al.A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-beta pathology and cognitive decline[J].SIGNAL TRANSDUCTION AND TARGETED THERAPY.2021,6(1):doi:10.1038/s41392-021-00748-4.
APA：
Rongcan Luo,Yu Fan,Jing Yang,Maosen Ye,Deng-Feng Zhang...&Yong-Gang Yao.(2021).A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-beta pathology and cognitive decline.SIGNAL TRANSDUCTION AND TARGETED THERAPY,6,(1)
MLA：
Rongcan Luo,et al."A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-beta pathology and cognitive decline".SIGNAL TRANSDUCTION AND TARGETED THERAPY 6..1(2021)
医学