Abstract
Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging.
Highlights
Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age
oculopharyngeal muscular dystrophy (OPMD) is a monogenic disorder and its etiology is found in an alanine expansion mutation in the gene encoding for poly-adenylate (poly(A)) binding protein nuclear 1 (PABPN1) (Brais et al, 1998)
A genome-wide shift from distal to proximal alternative polyadenylation site (PAS) and accumulation of shortened transcripts were found in the mouse model for OPMD, A17.1, which was generated by expPABPN1 overexpression in muscles, and in cells with reduced poly-adenylate RNA binding protein1 (PABPN1) expression
Summary
Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. This suggests that in addition to the fundamental genetic defect(s), possible similar aging-associated regulators trigger the late onset of symptoms and progression thereof. It was suggested that muscle symptoms in OPMD are caused by a PABPN1 gain-of-function.
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