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Circular RNAs as the molecular driver of Alzheimer’ s disease

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandling

The Ph.D. project aims to discover the role of circular RNA (circRNA), a non-coding RNA family, in human neurodegenerative diseases (NDs), especially in Alzheimer's disease (AD). A genome-wide circRNA profiling was performed on a large public AD cohort, the Mount Sinai Brain Bank (MSBB), to provide an overview of the transcriptomic change of circRNAs in AD. The MSBB data set contains data from four AD-affected brain regions, and we found hundreds of circRNAs to be differentially expressed (DE) with increased AD severity. The dysregulated circRNAs were enriched for biological pathways of critical neurological function, suggesting that circRNAs could contribute to the AD pathology.

Given that heritability is an important risk factor for AD, we further examined the genetic effect on circRNAs in the MSBB data set. We identified numerous circRNA expression quantitative trait loci (eCircQTLs), many of which were also splicing QTLs (sQTLs) for the host genes, suggesting a correlation between alternative splicing (AS) and circRNA expression in AD. Interestingly, we found that the amount of eCircQTLs is not associated with eQTLs for the linear counterpart of the circRNAs (and sometimes even the host genes), also indicating an independent genetic regulation of the circRNAs. Further enrichment tests based on cell-specific data implied that this independent genetic regulation was enriched in circRNAs that were abundant in neurons. These discoveries provide new insights into the genetic architecture of circRNA expression in human AD.

Our findings on circRNA expression in AD motivated us to investigate a role for circRNAs in other common neurological diseases since many abnormal phenotypes and malfunctional molecular mechanisms are shared in brain diseases. Using the public data sets of two neurodegenerative diseases: AD and amyotrophic lateral sclerosis (ALS), and two psychiatric diseases: autism spectrum disorder (ASD) and bipolar disease (BD), we didn't observe a common dysregulated pattern of circRNAs in the brain diseases, revealing that different disease types have distinct circRNA expression. Overall, the project offered a comprehensive investigation of circRNAs as contributors and possible biomarkers for AD and set the stage for future studies of circRNAs in human brain diseases.
OriginalsprogEngelsk
UdgivelsesstedAarhus
ForlagAarhus Universitet
Antal sider91
StatusUdgivet - jul. 2020

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