PABPN1: molecular function and muscle disease

Abstract

The polyadenosine RNA binding protein, polyadenylate-binding nuclear protein 1 (PABPN1), plays key roles in post-transcriptional processing of RNA. Although PABPN1 is ubiquitously expressed and presumably contributes to control of gene expression in all tissues, mutation of the PABPN1 gene causes the disease Oculopharyngeal Muscular Dystrophy (OPMD), in which a limited set of skeletal muscles are effected. A major goal in the field of OPMD research is to understand why mutation of a ubiquitously expressed gene leads to a muscle-specific disease. PABPN1 plays a well-documented role in controlling the poly(A) tail length of RNA transcripts but new functions are emerging through studies that exploit a variety of unbiased screens as well as model organisms. This review addresses: (1) the molecular function of PABPN1 incorporating recent findings that reveal novel cellular functions for PABPN1 and (2) the approaches that are being used to understand the molecular defects that stem from expression of mutant PABPN1. The long-term goal in this field of research is to understand the key molecular functions of PABPN1 in muscle as well as the mechanisms that underlie the pathological consequences of mutant PABPN1. Armed with this information, researchers can seek to develop therapeutic approaches to enhance the quality of life for patients afflicted with OPMD.

Poly(A) Tail-Mediated Gene Regulation by Opposing Roles of Nab2 and Pab2 Nuclear Poly(A)-Binding Proteins in Pre-mRNA Decay

“…Although the reasons for the strikingly different phenotypes related to Nab2 deficiency between budding and fission yeasts are unclear, the presence of an additional nuclear PABP in S. pombe (Pab2) may be one explanation. Nab2 is the major nuclear PABP in S. cerevisiae, as the genome of S. cerevisiae does not encode a homolog of S. pombe Pab2/human PABPN1 (47,48). In contrast, Pab2 is the more abundant nuclear PABP in S. pombe, with approximately 5,830 molecules of Pab2 and 2,745 molecules of Nab2 reported per proliferating cell (49).…”

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

“…The characteristic feature of OPMD is the presence of filamentous intranuclear inclusions made of mPABPN1 and resistant to KCl treatment [128]. Although the exact pathological mechanism underlying OPMD is still poorly understood, a body of evidence suggests that it is associated, at least in part, with the formation of aggregates and especially of oligomers or micro-aggregates made by the mutant proteins [129,130]. Although probably all the skeletal muscles are affected, the histologic changes are however most pronounced in a limited set of skeletal muscles (i.e.…”

“…extraocular, lingual, pharyngeal and diaphragmatic muscles) [128]. OPMD usually starts in the fifth or sixth decade of life with the main symptoms being eyelid drooping and difficulty in swallowing due to a weakness in the levator palpebrae superioris and pharyngeal muscles, respectively [129]. The disease does not shorten the life expectancy of the affected patients; it however significantly impairs the quality of their life due to frequent aspiration pneumonia and difficulties in swallowing which lead to malnutrition [128].…”

“…PABPN1 is a nuclear ubiquitously expressed multifunctional protein which is involved in pre-mRNA polyadenylation, transcription regulation, and mRNA nucleocytoplasmic transport in presumably all tissues [129]. It is a 306 residue multi-domain protein (MM~32.8 kDa) (Fig.…”

“…It is a 306 residue multi-domain protein (MM~32.8 kDa) (Fig. 7A) that can be divided in three domains [128,129]. (i) An acidic N-terminus domain (residues 1e161) starts with a stretch of 10 alanines.…”