ArticlePloS one2009
Hsp70 chaperones and type I PRMTs are sequestered at intranuclear inclusions caused by polyalanine expansions in PABPN1.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 44 citations in OpenAlex.
- Oculopharyngeal Muscular Dystrophy: From Molecular Pathogenesis to Gene Therapy.Molecular neurobiology · 2026Review
- The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response.Open biology · 2023Article
- Article
- Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy.Acta neuropathologica · 2022Article
- Pharyngeal pathology in a mouse model of oculopharyngeal muscular dystrophy is associated with impaired basal autophagy in myoblasts.Frontiers in cell and developmental biology · 2022Article
- Toxicity of internalized polyalanine to cells depends on aggregation.Scientific reports · 2021Article
- Inhibition of Myostatin Reduces Collagen Deposition in a Mouse Model of Oculopharyngeal Muscular Dystrophy (OPMD) With Established Disease.Frontiers in physiology · 2020Article
- Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy.Laboratory investigation; a journal of technical methods and pathology · 2019Article
- Established PABPN1 intranuclear inclusions in OPMD muscle can be efficiently reversed by AAV-mediated knockdown and replacement of mutant expanded PABPN1.Human molecular genetics · 2019Article
- Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648.Cell death & disease · 2019Article
- Proteomic analysis reveals that wildtype and alanine-expanded nuclear poly(A)-binding protein exhibit differential interactions in skeletal muscle.The Journal of biological chemistry · 2019Article
- Inhibitors of Protein Methyltransferases and Demethylases.Chemical reviews · 2018Review
- Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).Journal of medicinal chemistry · 2018Article
- Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing.Nucleic acids research · 2017Article
- Novel mouse models of oculopharyngeal muscular dystrophy (OPMD) reveal early onset mitochondrial defects and suggest loss of PABPN1 may contribute to pathology.Human molecular genetics · 2017Article
- PABPN1 gene therapy for oculopharyngeal muscular dystrophy.Nature communications · 2017Article
- Protein quality control in the nucleus.Current opinion in cell biology · 2016Review
- A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3).Angewandte Chemie (International ed. in English) · 2015Article
- Selective inhibitors of protein methyltransferases.Journal of medicinal chemistry · 2015Article
- Association of polyalanine and polyglutamine coiled coils mediates expansion disease-related protein aggregation and dysfunction.Human molecular genetics · 2014Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genomic instability at loci with tandem arrays of simple repeats is the cause for many neurological, neurodegenerative and neuromuscular diseases. When located in coding regions, disease-associated expansions of trinucleotide repeats are translated into homopolymeric amino acid stretches of glutamine or alanine. Polyalanine expansions in the poly(A)-binding protein nuclear 1 (PABPN1) gene causes oculopharyngeal muscular dystrophy (OPMD). To gain novel insight into the molecular pathophysiology of OPMD, we studied the interaction of cellular proteins with normal and expanded PABPN1. Pull-down assays show that heat shock proteins including Hsp70, and type I arginine methyl transferases (PRMT1 and PRMT3) associate preferentially with expanded PABPN1. Immunofluorescence microscopy further reveals accumulation of these proteins at intranuclear inclusions in muscle from OPMD patients. Recombinant PABPN1 with expanded polyalanine stretches binds Hsp70 with higher affinity, and data from molecular simulations suggest that expansions of the PABPN1 polyalanine tract result in transition from a disordered, flexible conformation to a stable helical secondary structure. Taken together, our results suggest that the pathological mutation in the PABPN1 gene alters the protein conformation and induces a preferential interaction with type I PRMTs and Hsp70 chaperones. This in turn causes sequestration in intranuclear inclusions, possibly leading to a progressive cellular defect in arginine methylation and chaperone activity.
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