The regulation of AβPP expression by RNA-binding proteins

Abstract

Amyloid β-protein precursor (AβPP) is cleaved by β- and γ-secretases to liberate amyloid beta (Aβ), the predominant protein found in the senile plaques associated with Alzheimer's disease (AD) and Down syndrome (Masters et al., 1985). Intense investigation by the scientific community has centered on understanding the molecular pathways that underlie the production and accumulation of Aβ Therapeutics that reduce the levels of this tenacious, plaque-promoting peptide may reduce the ongoing neural dysfunction and neuronal degeneration that occurs so profoundly in AD. AβPP and Aβ production are highly complex and involve still to be elucidated combinations of transcriptional, post-transcriptional, translational and post-translational events that mediate the production, processing and clearance of these proteins. Research in our laboratory for the past two decades has focused on the role of RNA binding proteins (RBPs) in mediating the post-transcriptional as well as translational regulation of APP messenger RNA (mRNA). This review article summarizes our findings, as well as those from other laboratories, describing the identification of regulatory RBPs, where and under what conditions they interact with APP mRNA and how those interactions control AβPP and Aβ synthesis.

Figure 1

Post-transcriptional gene regulation and APP mRNA. APP mRNA contains two translational (IRE and guanine-rich), one stabilizing (52-base), two destabilizing (29- and 81-base) and two cytoplasmic polyadenylation elements. ➀An IRE is located in the 5’-UTR of APP mRNA and translation is repressed when IRP1 is bound. ➁FMRP and hnRNP C compete for binding to the guanine-rich region in the CR of APP mRNA. Translation is repressed when FMRP is bound and active when hnRNP C is bound. The remaining, identified cis-elements in APP mRNA are located in the 3’-UTR. ➂Several proteins (nucleolin, YB1, La, PAI-RBP1, EF1α and RCK/p54) form a complex at a 52-be stabilizing element adjacent to the stop codon. YB1 and La interact directly with the message. RCK/p54 is a component of P-bodies along with Ago1 and Ago2. FMRP interacts with RCK/p54 suggesting that FMRP represses translation by recruiting APP mRNA to P-bodies. ➃hnRNP C and nucleolin bind to a 29-be element approximately 200 bases downstream from the stop codon. When hnRNP C is bound, APP mRNA is stable whereas nucleolin increases decay. As FMRP is a known binding partner of both nucleolin and YB1, these data suggest that a large ribonucleoprotein complex forms to bring multiple cis-regulatory elements of APP mRNA in close proximity to mediate post-transcriptional events. ➄An 81-nt destabilizing element is located further downstream in the 3’-UTR. The identity of the RBPs that binds to this cis-element has yet to be determined. ➅,➆Two CPEs are located near the poly(A) tail in APP mRNA and interact with the polyadenylation machinery. Both sites are utilized, but the longer mRNA exhibits more efficient ribosome mobilization and translation. RBPs that interact directly with APP mRNA are depicted as oval-shaped whereas those that bind through protein/protein interactions are rectangular in shape.