Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology
Yubo Cheng,
Luke Saville,
Babita Gollen,
Christopher Isaac,
Abel Belay,
Jogender Mehla,
Kush Patel,
Nehal Thakor,
Majid H Mohajerani,
Athanasios Zovoilis
Affiliations
Yubo Cheng
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada; Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, Canada
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada; Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, Canada
Babita Gollen
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada; Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, Canada
Christopher Isaac
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada; Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, Canada
Abel Belay
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada; Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, Canada
Jogender Mehla
Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada
Kush Patel
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada
Nehal Thakor
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada; Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, Canada; Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada; Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, Canada
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).
