Oculopharyngeal muscular dystrophy: Recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. OPMD is caused by a small expansion of a short polyalanine tract in the poly (A) binding protein nuclear 1 protein (PABPN1). The mechanism by which the polyalanine expansion mutation in PABPN1 causes disease is unclear. PABPN1 is a nuclear multi-functional protein which is involved in pre-mRNA polyadenylation, transcription regulation, and mRNA nucleocytoplasmic transport. The distinct pathological hallmark of OPMD is the presence of filamentous intranuclear inclusions (INIs) in patient's skeletal muscle cells. The exact relationship between mutant PABPN1 intranuclear aggregates and pathology is not clear. OPMD is a unique disease sharing common pathogenic features with other polyalanine disorders, as well as with polyglutamine and dystrophic disorders. This chapter aims to review the rapidly growing body of knowledge concerning OPMD. First, we outline the background of OPMD. Second, we compare OPMD with other trinucleotide repeat disorders. Third, we discuss the recent advances in the understanding of the molecular mechanisms underlying OPMD pathogenesis. Finally, we review recent therapeutic strategies for OPMD.

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

“…The most common form of oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease that is caused by the expansion of GCG trinucleotide repeats in the coding sequence of the polyadenylate-binding protein nuclear 1 (PABPN1), translated into a poly(Ala) stretch [128]. The wild-type protein bears 10 alanines at its N-terminus; mutant proteins (mPABPN1) in which the polyA tract is extended to 12e17 residues cause the disease and the longer the tract the more severe the disease [128].…”

“…The wild-type protein bears 10 alanines at its N-terminus; mutant proteins (mPABPN1) in which the polyA tract is extended to 12e17 residues cause the disease and the longer the tract the more severe the disease [128]. The characteristic feature of OPMD is the presence of filamentous intranuclear inclusions made of mPABPN1 and resistant to KCl treatment [128].…”

“…The wild-type protein bears 10 alanines at its N-terminus; mutant proteins (mPABPN1) in which the polyA tract is extended to 12e17 residues cause the disease and the longer the tract the more severe the disease [128]. 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].…”

“…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]. The largest OPMD cluster is in French-Canadian population with an estimated prevalence of 1:1,000; in Europe, the estimated prevalence is 1:100,000 [128].…”