Alzheimer's disease associated AKAP9 I2558M mutation alters posttranslational modification and interactome of tau and cellular functions in CRISPR-edited human neuronal cells.
Yang YouSamuel W HershRoshanak AslebaghScott A ShafferSeiko IkezuJesse MezKathryn L LunettaMark W LogueLindsay A FarrerTsuneya IkezuPublished in: Aging cell (2022)
Alzheimer's disease (AD) is a pervasive neurodegeneration disease with high heritability. In this study, we employed CRISPR-Cas9-engineered technology to investigate the effects of a rare mutation (rs144662445) in the A kinase anchoring protein 9 (AKAP9) gene, which is associated with AD in African Americans (AA), on tau pathology and the tau interactome in SH-SY5Y P301L neuron-like cells. The mutation significantly increased the level of phosphorylated tau, specifically at the site Ser396/Ser404. Moreover, analyses of the tau interactome measured by affinity purification-mass spectrometry revealed that differentially expressed tau-interacting proteins in AKAP9 mutant cells were associated with RNA translation, RNA localization and oxidative activity, recapitulating the tau interactome signature previously reported with human AD brain samples. Importantly, these results were further validated by functional studies showing a significant reduction in protein synthesis activity and excessive oxidative stress in AKAP9 mutant compared with wild type cells in a tau-dependent manner, which are mirrored with pathological phenotype frequently seen in AD. Our results demonstrated specific effects of rs14462445 on mis-processing of tau and suggest a potential role of AKAP9 in AD pathogenesis.
Keyphrases
- cerebrospinal fluid
- crispr cas
- induced apoptosis
- oxidative stress
- genome editing
- mass spectrometry
- wild type
- endothelial cells
- cognitive decline
- signaling pathway
- ischemia reperfusion injury
- gene expression
- binding protein
- small molecule
- ms ms
- cell proliferation
- protein kinase
- risk assessment
- tyrosine kinase
- induced pluripotent stem cells
- resting state
- brain injury
- liquid chromatography
- human health
- transcription factor
- heat stress