Circular RNA Encoded Amyloid Beta peptides-A Novel Putative Player in Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (A?) play a crucial role in the pathology of AD. In familial AD, A? 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 A? biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the A?-coding region of the APP gene termed circA?-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 circA?-a is efficiently translated into a novel A?-containing A?175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, A?175 was shown to be processed into A? peptides-a hallmark of AD. In summary, our analysis revealed an alternative pathway of A? biogenesis. Consequently, circA?-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.

SUBMITTER: Mo D 

PROVIDER: S-EPMC7650678 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature