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Mechanisms underlying circular RNA biogenesis in Alzheimer’s disease related genes

阿尔茨海默病相关基因中环状 RNA 生物发生的机制

基本信息

批准号：
10665204
负责人：
Paul Nils Valdmanis
金额：
$ 22.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665204
关键词：
Affect Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid beta-Protein Biogenesis Brain Cell Line Cells Code Complement Disease Etiology Evaluation Event Exons Generations Genes Genetic Transcription High-Throughput RNA Sequencing Hippocampus Human Hypoxia In Vitro Individual Knowledge Large-Scale Sequencing Late Onset Alzheimer Disease Mediating Messenger RNA Neurodegenerative Disorders Neurons Oxidative Stress Pathogenesis Pathogenicity Pathology Patients Prevalence Process Production Protein Isoforms Proteins RNA RNA Helicase RNA Splicing Regulation Regulatory Element Repetitive Sequence Role Sampling Series Study models Synapses Synaptosomes Testing Therapeutic Tissues Transcript Translations Untranslated RNA Variant abeta accumulation brain tissue circular RNA design differential expression effective therapy frontal lobe glycogen synthase kinase 3 beta glycogen synthase kinase 3 beta inhibitor mRNA Translation mouse model novel novel therapeutic intervention physiologic stressor presenilin-2 preservation prevent repository tau Proteins tau aggregation tau expression tau-1 transcriptome transcriptome sequencing vector

项目摘要

Alzheimer’s disease (AD) is a debilitating and pervasive neurodegenerative disorder with no effective treatments and is predicted to double in prevalence over the next 30 years. One of the first hallmarks of AD is loss of synapses followed by amyloid beta aggregation and tau neurofibrillary tangles. The steps leading to these aggregation events, especially in individuals with late-onset AD, are poorly understood. To better comprehend the transcriptional mechanisms associated with synapse loss, we isolated synapses in the form of synaptosomes and performed high throughput RNA sequencing. We found differentially expressed mRNAs associated with the synapse in AD patients with implications for synaptic transport and local mRNA translation. Notably, when interrogating the noncoding transcriptome, we found a widespread shift of distribution of circular RNAs (circRNAs) from cell bodies to synapses. CircRNAs are stable molecules formed from covalent linkages of conserved back-spliced exon junctions that can compete with linear counterparts. Interestingly among the top differentially expressed circRNAs were two circRNAs from GSK3β, which underwent a switch from one isoform significantly upregulated in AD to another significantly downregulated. GSK3β phosphorylation of tau is essential for its aggregation and GSK3β inhibitors have actively been pursued as translational targets for AD. Further evaluation of GSK3β and other circular RNAs in a large RNAseq repository revealed differentially expressed circRNAs in PSEN2 surrounding exons associated with hypoxia mediated alternative splicing. Therefore, key AD associated proteins have RNA counterparts at the synapse that are differentially expressed that may have critical modulatory roles. Our findings point to a novel mode of regulation at the RNA level. Through a series of in vitro studies and mouse models of tau pathology, we propose to therapeutically modulate the expression of circGSK3B and circPSEN2 isoforms to restore appropriate regulation of tau. We propose to ascertain whether regulatory features surrounding alternative GSK3β exons affect circRNA production and whether RNA helicases influence the GSK3β circRNA isoform switch that we observe. In addition, we will evaluate the relationship between PSEN2 circRNA biogenesis and the role of oxidative stress in affecting aberrant PSEN2 alternative splicing – a phenomenon we observe to be significantly enriched in sporadic AD. Collectively, we will leverage our understanding of the rules governing circRNA biogenesis and regulation to generate molecules capable of preserving appropriate expression of GSK3β and prevent tau aggregation.

阿尔茨海默病（AD）是一种使人衰弱和普遍存在的神经退行性疾病