Abstract
The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here, we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer's disease (AD).
Highlights
The number of patients with Alzheimer’s disease (AD) is expected to skyrocket in the upcoming years (Cornutiu, 2015)
We investigate whether B2-stress response genes (SRGs) are deregulated during amyloid pathology, which would imply a role for B2 RNAs in this condition and we examine whether amyloid toxicity is connected with changes in B2 RNA processing
We have identified genomic locations that are subject to regulation by small interspersed nuclear elements (SINEs) B2 non-coding RNAs during response to thermal stress through binding and suppression of transcription by the RNA Pol II at the pre-stimulus state
Summary
The number of patients with Alzheimer’s disease (AD) is expected to skyrocket in the upcoming years (Cornutiu, 2015). Among the genes that have been implicated in transcriptome-environment interactions are stress response genes (SRGs) (Gallo et al, 2018). These genes have been initially described in other biological contexts, such as thermal and oxidative stress, as pro-survival genes activated early after the application of a stress stimulus, such as heat shock, that help the cell overcome the stress condition (Mahat et al, 2016). In addition to the cellular response to stress, many SRGs were shown to have a central role in the function of the mouse hippocampus, by mediating cell signaling and genome-environment interactions. We and others have shown that in the healthy hippocampus during
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