G.O.5

• Published in: Neuromuscular disorders : NMD Vol. 24; no. 9; pp. 793 - 794
• Main Authors: Trollet, C, Chartier, A, Klein, P, Barbezier, N, Gidaro, T, Casas, F, Carberry, S, Dowling, P, Maynadier, L, Dickson, G, Mouly, V, Ohlendieck, K, Butler-Browne, G, Simonelig, M
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• Subjects: Neurology
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2014.06.013

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant inherited, slow progressing, late onset degenerative muscular disorder where a small group of specific muscles – pharyngeal and eyelid muscles – are primarily affected, leading to dysphagia and ptosis. Its genetic basis is a trinucleotide repeat expansion ranging from (GCG)8 to (GCG)13 in the N-terminus polyalanine domain of the poly(A) binding protein nuclear 1 (PABPN1) gene. Mutated expanded PABPN1 protein accumulates as insoluble nuclear inclusions in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and in the regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Using a Drosophila model of OPMD, we found that OPMD pathogenesis depends on affected poly(A) tail length regulation of specific mRNAs. We identified a set of mRNAs encoding mitochondrial proteins that are down-regulated during OPMD progression. Reduced levels of these mRNAs correlate with their shortened poly(A) tails. Partial rescue of the levels of these mRNAs when deadenylation is decreased using a deadenylase mutant improves mitochondrial function and reduces muscle weakness. Interestingly, the down-regulation of these mRNAs already occurs in the earliest stages of disease progression, indicating that this defect is one of the first molecular defects in OPMD. Importantly, the down-regulation of mRNAs encoding mitochondrial proteins has been validated in a transgenic mouse model of OPMD. Moreover, a proteomic approach has also validated the down-regulation of mitochondrial proteins in clinically nonaffected muscles of OPMD patients. We propose a model where one of the primary defect in OPMD corresponds to defective poly(A) tail regulation of specific mRNAs encoding mitochondrial proteins, leading to decreased synthesis of mitochondrial proteins and defective mitochondrial activity.