A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline
Authors:
Open Access
- 31 August 2021
- journal article
- research article
- Published by Springer Nature in Signal Transduction and Targeted Therapy
- Vol. 6 (1) , 1-16
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.Keywords
This publication has 112 references indexed in Scilit:
- Neurotoxicity of Amyloid -Protein: Synaptic and Network DysfunctionCold Spring Harbor Perspectives in Medicine, 2012
- Autophagy failure in Alzheimer's disease—locating the primary defectNeurobiology of Disease, 2011
- Peroxisomal alterations in Alzheimer’s diseaseActa Neuropathologica, 2011
- APOE and Alzheimer disease: a major gene with semi-dominant inheritanceMolecular Psychiatry, 2011
- A framework for variation discovery and genotyping using next-generation DNA sequencing dataNature Genetics, 2011
- Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 MutationsCell, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid betaProceedings of the National Academy of Sciences, 2009
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences, 2005
- Clinical diagnosis of Alzheimer's diseaseNeurology, 1984