Circular RNA Encoded Amyloid Beta peptides-A Novel Putative Player in Alzheimer's Disease.
Dingding MoXinping LiCarsten A RaabeTimofey S RozhdestvenskyBoris V SkryabinJuergen BrosiusPublished in: Cells (2020)
Alzheimer's disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of Aβ biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the Aβ-coding region of the APP gene termed circAβ-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-containing Aβ175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, Aβ175 was shown to be processed into Aβ peptides-a hallmark of AD. In summary, our analysis revealed an alternative pathway of Aβ biogenesis. Consequently, circAβ-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates.
Keyphrases
- mild cognitive impairment
- cognitive decline
- amino acid
- end stage renal disease
- copy number
- ejection fraction
- induced apoptosis
- newly diagnosed
- cognitive impairment
- endothelial cells
- gene expression
- single cell
- heat shock protein
- signaling pathway
- resting state
- functional connectivity
- late onset
- machine learning
- artificial intelligence
- peritoneal dialysis
- transcription factor
- oxidative stress
- cell cycle arrest
- patient reported outcomes
- early onset
- endoplasmic reticulum stress