Dataset Information

Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.

ABSTRACT: Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.

SUBMITTER: Chartier A

PROVIDER: S-EPMC4376527 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.

Chartier Aymeric A Klein Pierre P Pierson Stéphanie S Barbezier Nicolas N Gidaro Teresa T Casas François F Carberry Steven S Dowling Paul P Maynadier Laurie L Bellec Maëlle M Oloko Martine M Jardel Claude C Moritz Bodo B Dickson George G Mouly Vincent V Ohlendieck Kay K Butler-Browne Gillian G Trollet Capucine C Simonelig Martine M

PLoS genetics 20150327 3

Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly ...[more]

PMID: 25816335

Similar Datasets

Project description:Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.

Project description:BACKGROUND:Although dysphagia represents a hallmark manifestation of oculopharyngeal muscular dystrophy (OPMD), limited knowledge exists regarding the underlying nature of oropharyngeal swallowing impairments in this patient population. We aimed to delineate global pharyngeal dysphagia profiles in OPMD and identify the prevalence and physiologic associations of impairments in swallowing safety and efficiency. METHODS:Twenty-two individuals with OPMD completed a videofluoroscopic swallowing evaluation. Blinded raters completed validated scales of global dysphagia (dynamic imaging grade of swallowing toxicity, DIGEST), efficiency (normalized residue ratio scale, NRRS), and safety (penetration-aspiration scale, PAS). Degree of laryngeal vestibule closure and aspiration events were described. Descriptives and chi-squared analyses were conducted with alpha set at P < .05. KEY RESULTS:One hundred and thirty-four swallowing trials were analyzed. DIGEST scores revealed that 96% (n = 21) of participants demonstrated pharyngeal dysphagia (score >1). Presence of a cricopharyngeal bar was noted in 10 individuals. The predominant swallowing categorization across patients was safe and inefficient (51%) followed by unsafe and inefficient (32%). 77.3% demonstrated vallecular residue (NRRSv>0.07) and 90.1% piriform sinus residue (NRRSp > .20). 33% (n = 54) of swallows were unsafe (PAS>3) with 45 episodes of penetration and 9 episodes of aspiration. Aspiration occurred during the swallow in 100% of identified occurrences. Incomplete epiglottic inversion was associated with airway compromise and postswallow residue (P < .05). CONCLUSIONS & INFERENCES:These findings highlight the high prevalence of oropharyngeal swallowing impairments in both swallowing efficiency and safety. A high proportion of physiologic impairments in epiglottic inversion and laryngeal vestibule closure were noted that related to functional impairments in swallow safety and inefficiency.

Dataset Information

Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.

Publications

Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets