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:
  • 金额:
    $ 22.77万
  • 依托单位:
  • 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

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

项目成果

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Paul Nils Valdmanis其他文献

Paul Nils Valdmanis的其他文献

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{{ truncateString('Paul Nils Valdmanis', 18)}}的其他基金

Novel approaches to identify tandem repeat expansions in neurodegenerative disease
识别神经退行性疾病串联重复扩增的新方法
  • 批准号:
    10440935
  • 财政年份:
    2022
  • 资助金额:
    $ 22.77万
  • 项目类别:
Novel approaches to identify tandem repeat expansions in neurodegenerative disease
识别神经退行性疾病串联重复扩增的新方法
  • 批准号:
    10593996
  • 财政年份:
    2022
  • 资助金额:
    $ 22.77万
  • 项目类别:

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