A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease,impairs lysosomal function,and facilitates amyloid-p pathology and cognitive decline
作者机构：Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences&Yunnan Provinceand KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina Kunming College of Life ScienceUniversity of Chinese Academy of SciencesKunmingYunnanChina State Key Laboratory of Genetic Resources and EvolutionKunming Institute of ZoologyChinese Academy of SciencesKunmingChina Department of PsychiatryThe First Affiliated Hospital of Kunming Medical UniversityKunmingChina Division of Mood DisordersShanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina Mental Health Institute of the Second Xiangya HospitalCentral South UniverstyChangshaChina Center for Excellence in Animal Evolution and GeneticsChinese Academy of SciencesKunmingYunnanChina CAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghaiChina
出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)
年 卷 期：2021年第6卷第9期
页 面：2920-2935页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100203[医学-老年医学] 10[医学]
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.) the Training of High-Level Health Technical Personnel in Yunnan Province,Medical Academic Leader(D-2018047 to H.-Y.J.)
主 题：Alzheimer amyloid lysosomal
摘 要：Alzheimer’s disease(AD)is characterized by progressive synaptic dysfunction,neuronal death,and brain atrophy,with amyloid-p(Ap)plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue,which all lead to loss of cognitive *** 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 *** we identified a missense variant rs117916664(c.896TC,***299Ser[p.N299S])of the acetyl-CoA acyltransferase 1(ACM1)gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent *** 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 Ap pathology and neuronal loss,which finally caused cognitive impairment in a murine *** findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.
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