Exploring the regulatory roles of circular RNAs in Alzheimer's disease

Abstract

Circular RNAs (circRNAs) are a type of covalently closed, single-stranded circular noncoding RNA that can affect the expression of many protein-coding genes. Growing evidence has shown that circRNAs play critical roles in Alzheimer's disease (AD) and may have therapeutic potentials for this disease. CircRNAs play regulatory roles in neural functions and neurological disorders through diverse mechanisms, including acting as microRNA sponges or interacting with proteins to regulate selective splicing or transcription, as well as through epigenetic modification. In this review, we discuss the biogenesis and functions of circRNAs and the research progress on circRNAs in AD to advance the understanding of how circRNAs contribute to this neurological disorder.

Keywords: Alzheimer’s disease; Circular RNA; Function.

Fig. 1

Schematic of splicing of circRNAs. a Generally, linear mRNA is generated through canonical splicing. b Exonic circRNAs (ecircRNAs) are formed through back-splicing from a 5′ splice site (donor site) to a 3′ splice site (acceptor site), containing one exon. c EcircRNAs can also be formed to contain multiple exons, with the intron between two axons removed, thus bringing the 5′ splice site of one exon close to the 3′ splice site of the other exon. d If intron is retained with two exons, an exon-intron circRNA (EIciRNA) is formed. e Circular intronic RNAs (ciRNAs) are the closed-loop structure produced by lariat intron excised from pre-mRNA after pairing with reverse complementary sequences. f tricRNA is generated via a 3′-5′ phosphodiester bond between termini of introns that are removed from pre-tRNA by tRNA splicing enzymes.

Fig. 2

Functions of circRNAs. a CircRNAs are formed from pre-mRNAs and have endogenous effects on linear RNA transcription. This effect can be promoting or suppressing the transcription of linear RNAs. b CircRNAs bind to RBPs to influence mRNA transcriptional levels. c EIciRNAs can enhance gene transcription via interacting with U1 snRNP and RNA polymerase II in the promoter region of the host gene. d CircRNAs function as miRNA sponges to bind to miRNAs and inhibit target mRNAs degradation. e circMbl can interact with MBL, and act as a negative feedback regulation between MBL and circMbl production. When MBL is in excess, it binds to the mbl pre-mRNA and causes it to backsplice into circMbl. When MBL protein concentration are reduced due to MBL binding to circMb1, the production of circMbl is reduced. f CircRNAs containing an open reading frame (ORF) driven by the IRES can translate a functional protein. g CircRNAs function as mRNA trap to influence mRNA splicing and protein translation