Role of R-loops in transcriptional stress, genome instability, and chronic immune response in Alzheimer's disease

点击翻译按钮获取中文摘要

Advanced age is a major risk factor for many chronic diseases, including Alzheimer’s disease (AD). Despite substantial research progress, most treatments currently available merely mitigate symptoms. Given that most of patients with dementia due to AD are sporadic, and in those, aging is the key risk factor for this late-onset AD, targeting the mechanisms that have been collectively summarized as “hallmarks of aging” may provide avenues for development of new therapeutic approaches. Emerging evidence links aging and age-related neurodegenerative diseases to disruption in RNA alterations, specifically N6-methyladenosine (m6A) modification. m6A RNA is the most prevalent and abundant modification of RNA in eukaryotes, with high expression specifically in the brain. Recently, m6A RNA has been shown to regulate stability of R-loops; three- nucleic acid structures, consisting of an RNA-DNA hybrid and a ssDNA that form during transcription. In this proposal we will examine the role of m6A epi-transcriptomic modification in R-loop-driven pathophysiology of AD. Using Drosophila AD model, in aim 1 we will elucidate how m6A RNA impairment impacts R-loop distribution across the genome and formation of RNA-DNA hybrids in cytoplasm, and their impact on transcriptional stress and activation of chronic immune response in AD. The significance of aim 2 is in identifying the regulatory mechanisms of R-loop-dependent DSB formation in AD. While variety of exogenous factors can contribute to DNA damage, we will define a role of R-loops in genome instability associated with AD. Moreover, we will define the epigenetic modifications associated with formation of stable R-loops resistant to resolution, which are alternatively processed into DSBs. In aim 3, we will expand our studies from Drosophila to mammalian system. Using in vitro rat cortical neuron cultures seeded with human brain tau, we will further elucidate the molecular mechanisms of R-loop associated genome instability and neuroinflammation in AD. Neurons have specialized RNA metabolism and it is therefore not surprising that dysfunction in RNA metabolism is strongly associated with neurological diseases. This proposal focuses on a novel possibility that defects in RNA metabolism, and particularly R-loop homeostasis, is a significant driver of transcriptional stress, genome instability, and chronic immune response; key hallmarks of aging, whose acceleration may lead to neurodegeneration.