ArticlePLoS genetics2015
Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 75 citations in OpenAlex.
- Oculopharyngeal Muscular Dystrophy: From Molecular Pathogenesis to Gene Therapy.Molecular neurobiology · 2026Review
- Insights into the heterogeneity of oculopharyngeal muscular dystrophy.Neurogenetics · 2025Article
- Polyalanine Expansion in PABPN1 Alters the Structure and Dynamics of Its Nuclear Aggregates in Differentiated Muscle Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Plasma-derived protein and imaging biomarkers distinguish disease severity in oculopharyngeal muscular dystrophy.Journal of neuromuscular diseases · 2025Article
- Different outcomes of endurance and resistance exercise in skeletal muscles of Oculopharyngeal muscular dystrophy.Journal of cachexia, sarcopenia and muscle · 2024Article
- Spatial organization of translation and translational repression in two phases of germ granules.Nature communications · 2024Article
- Program with last minute abstracts of the Padua Days on Muscle and Mobility Medicine, 27 February - 2 March, 2024 (2024Pdm3).European journal of translational myology · 2024Article
- A fatty acid anabolic pathway in specialized-cells sustains a remote signal that controls egg activation in Drosophila.PLoS genetics · 2024Article
- Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2.Acta neuropathologica · 2024Article
- RNA binding proteins Smaug and Cup induce CCR4-NOT-dependent deadenylation of the nanos mRNA in a reconstituted system.Nucleic acids research · 2023Article
- The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response.Open biology · 2023Article
- Bidirectional roles of the Ccr4-Not complex in regulating autophagy before and after nitrogen starvation.Autophagy · 2023Article
- Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy.Acta neuropathologica · 2022Article
- Translesion DNA synthesis-driven mutagenesis in very early embryogenesis of fast cleaving embryos.Nucleic acids research · 2022Article
- Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy.PLoS genetics · 2022Article
- BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy.Molecular therapy. Nucleic acids · 2021Article
- Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- Translating around the clock: Multi-level regulation of post-transcriptional processes by the circadian clock.Cellular signalling · 2021Review
- The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases.Antioxidants (Basel, Switzerland) · 2020Review
- Regulation of the RNA-binding protein Smaug by the GPCR Smoothened via the kinase Fused.EMBO reports · 2020Article
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Authors and funding
19 authors at 10 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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