A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline
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...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-08-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-021-00748-4 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 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 |
| author_facet |
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 |
| author_sort |
Rongcan Luo |
| title |
A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline |
| title_short |
A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline |
| title_full |
A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline |
| title_fullStr |
A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline |
| title_full_unstemmed |
A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline |
| title_sort |
novel missense variant in acaa1 contributes to early-onset alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline |
| publisher |
Nature Publishing Group |
| series |
Signal Transduction and Targeted Therapy |
| issn |
2059-3635 |
| publishDate |
2021-08-01 |
| description |
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. |
| url |
https://doi.org/10.1038/s41392-021-00748-4 |
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doaj-cbe67949e9ff47f799160047062a6bae2021-09-05T11:19:19ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352021-08-016111610.1038/s41392-021-00748-4A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive declineRongcan Luo0Yu Fan1Jing Yang2Maosen Ye3Deng-Feng Zhang4Kun Guo5Xiao Li6Rui Bi7Min Xu8Lu-Xiu Yang9Yu Li10Xiaoqian Ran11Hong-Yan Jiang12Chen Zhang13Liwen Tan14Nengyin Sheng15Yong-Gang Yao16Key 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 SciencesKey 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 SciencesKey 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 SciencesKey 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 SciencesKey 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 SciencesState Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of SciencesKey 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 SciencesKey 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 SciencesKey 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 SciencesKey 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 SciencesKey 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 SciencesKey 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 SciencesDepartment of Psychiatry, The First Affiliated Hospital of Kunming Medical UniversityDivision of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of MedicineMental Health Institute of the Second Xiangya Hospital, Central South UniversityState Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of SciencesKey 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 SciencesAbstract 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.https://doi.org/10.1038/s41392-021-00748-4 |