ArticleInternational neurourology journal2022
Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD.
Article in International neurourology journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Full-length single-cell spatial transcriptomics reveals spatial and cell-type-specific transcript isoforms in the primate brain.Nature methods · 2026Article
- Sex- and brain region-specific gene expression in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2026Article
- Prognostic analysis and risk assessment based on RNA editing in hepatocellular carcinoma.Journal of applied genetics · 2024Article
- Altered metabolism and DAM-signatures in female brains and microglia with aging.Brain research · 2024Article
- Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging.bioRxiv : the preprint server for biology · 2023Article
- Looking Forward to Saying Goodbye to COVID-19 and a Step Forward.International neurourology journal · 2022Article
- Epigenetic Dysfunction of Neurodegenerative Diseases, MeCP2 and More.International neurourology journal · 2022Article
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Abstract
purposeAlzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features.
methodsWe analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES.
resultsWe identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis.
conclusionThis study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD.
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