ReviewThe regulation of AβPP expression by RNA-binding proteins
Highlights
► Multiple RBPs interact with distinct cis-elements in APP mRNA. ► hnRNP C and nucleolin bind to 3′-UTR cis-elements and mediate message stability. ► IRP1 binds to an IRE in the 5′-UTR of APP mRNA to regulate translation. ► FMRP and hnRNP C compete for binding to a CR G-rich element to modulate translation. ► APP mRNA is subject to diverse post-transcriptional regulatory processes.
Introduction
The APP gene is located on human chromosome 21 and codes for AβPP, a ubiquitously expressed, transmembrane protein that localizes to post-synaptic densities, axons, dendrites and neuromuscular junctions (NMJ) (Akaaboune et al., 2000, Shigematsu et al., 1992), consistent with its multiple roles in cell adhesion (Soba et al., 2005), synapse formation (Torroja et al., 1999, Yang et al., 2005) and synapse maturation (Akaaboune et al., 2000). Differential processing of AβPP by non-amyloidogenic (α- and γ-) or amyloidogenic (β- and γ-) secretases produces soluble AβPP (sAβPPα and sAβPPβ), truncated or full-length amyloid-beta (Aβ) and variable length carboxy-terminal fragments (CTFs). The over-production and ultimate aggregation of Aβ is associated with AD and Down syndrome pathology with current evidence suggesting a more pathogenic role for soluble, pre-aggregated Aβ. Despite decades of investigation, much remains to be learned about the normal physiological function of Aβ and other AβPP catabolites as well as the cellular and molecular pathways that regulate their generation. Clearly, a better understanding of AβPP biology and gene expression will provide new avenues for therapeutic intervention in a number of highly prevalent and currently untreatable neurological disorders.
Our laboratory has studied the mechanisms that underlie the stability and translation of APP mRNA. These studies were triggered by the realization that the 3′ untranslated regions (3′ UTR) of mouse, rat, human and other species of APP mRNA contained islands of substantial homology, consistent with the presence of cis-acting elements. We hypothesized that APP mRNA was subject to activation-dependent changes in stability and/or translation. Such events could account for both increased mRNA under steady state levels as well as increased translation. Indeed, we and other groups have successfully defined multiple cis-regulatory elements within the 5′-UTR, coding region (CR) and 3′-UTR of APP mRNA that mediate the post-transcriptional stability and/or translation of APP mRNA (Zaidi and Malter, 1994, Amara et al., 1999, Rogers et al., 2002, Westmark et al., 2006, Westmark and Malter, 2007) as well as identified a number of RBPs that bind to these cis-elements (Zaidi et al., 1994, Zaidi and Malter, 1995, Westmark and Malter, 2007, Broytman et al., 2008, Lee et al., 2010, Cho et al., 2010). These mRNA/RBP complexes control the degradation, stability and/or translation of APP mRNA, which directly determines how much AβPP is synthesized and thus available for processing toward or away from amyloidogenic endpoints.
This review article summarizes our findings, as well as those from the Rogers, Amara and Gorospe laboratories, describing the mRNA/RBP complexes and signaling pathways that regulate AβPP expression. A detailed understanding of the molecular interactions that regulate AβPP synthesis may provide novel avenues for therapeutic intervention in the treatment of AD and other Aβ-related disorders.
Section snippets
cis-Regulatory elements in APP mRNA
mRNA stability is an important control point in gene expression. The mRNAs of certain classes of regulatory proteins, such as oncogenes, cytokines, lymphokines and transcriptional activators are extremely labile (Brewer, 1991, Shaw and Kamen, 1986). Many of these mRNAs contain a common AUUUA pentamer in their 3′-UTR, which confers message instability through interactions with RBPs, such as AU-rich binding factor (AUBF) (Malter, 1989, Gillis and Malter, 1991), AUF1 (Wang et al., 1998) or TTP (
RNA binding proteins that interact with APP mRNA
Given the numerous cis-elements described above, it is hardly surprising that multiple RBPs have been identified that interact with APP mRNA. Many of these proteins are known to bind to multiple mRNAs and have diverse functions including nuclear/cytoplasmic shuttling, RNA helicase activity, iron homeostasis and translational repression. Interestingly, with the exception of the 5′-UTR IRE-like domain, the cis-elements in APP mRNA do not show obvious or substantial homology to other mRNAs. As it
Post-transcriptional gene regulation of APP mRNA
Post-transcriptional gene regulation is a complex process involving interaction of cis-regulatory elements in the 3′-UTR of mRNAs with trans factors or RBPs. These interactions are regulated by cell signaling events and likely result in alterations in higher order structures of the mRNAs. A summary of the identified cis-regulatory elements and trans factors involved in the pos-transcriptional gene regulation of APP mRNA is depicted in Fig. 1. The role of microRNAs (miRNAs) is also evolving as
Translational regulation of APP mRNA
App mRNAs are highly associated with polyribosomes in rat brain (Denman et al., 1991) suggesting that translational regulation could play an important role in AβPP production. At least two identified cis-elements regulate translation of APP mRNA including an IRE in the 5′-UTR (Rogers et al., 2002) and a guanine-rich element in the CR (Westmark and Malter, 2007, Lee et al., 2010). RBPs, which modulate ribosomal access and initiation, often mediate translational control at the synapse. Two of the
The need for new therapeutic approaches
The ultimate reason to understand the cellular and molecular pathways underlying AβPP and Aβ production is to facilitate the rationale development of reliable and safe therapeutics. All of the currently approved drugs for the treatment of AD act on healthy neurons to (1) compensate for reduced acetylcholine in the case of cholinesterase inhibitors, or (2) modulate NMDA receptor activity in the case of memantine. They improve cognitive ability for a year or less, but do not reduce amyloid plaque
Acknowledgments
This work was supported by the National Institutes of Health grants R01-AG10675, RO1-DA026067, P30-HD03352, T32-AG00213, the Alzheimer's Drug Discovery Foundation, FRAXA Research Foundation and the Wisconsin Comprehensive Memory Program. The sponsors had no role in the writing of this review article or the decision to publish. The authors thank Dr. Pamela Westmark for critical reading of the manuscript.
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