@article{eae66affe21648169a57a8e6994d0967,
title = "Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy",
abstract = "Oculopharyngeal muscular dystrophy (OPMD) is a rare muscle disease characterized by an onset of weakness in the pharyngeal and eyelid muscles. The disease is caused by the extension of a polyalanine tract in the Poly(A) Binding Protein Nuclear 1 (PABPN1) protein leading to the formation of intranuclear inclusions or aggregates in the muscle of OPMD patients. Despite numerous studies stressing the deleterious role of nuclear inclusions in cellular and animal OPMD models, their exact contribution to human disease is still unclear. In this study, we used a large and unique collection of human muscle biopsy samples to perform an in-depth analysis of PABPN1 aggregates in relation to age, genotype and muscle status with the final aim to improve our understanding of OPMD physiopathology. Here we demonstrate that age and genotype influence PABPN1 aggregates: the percentage of myonuclei containing PABPN1 aggregates increases with age and the chaperone HSP70 co-localize more frequently with PABPN1 aggregates with a larger polyalanine tract. In addition to the previously described PRMT1 and HSP70 co-factors, we identified new components of PABPN1 aggregates including GRP78/BiP, RPL24 and p62. We also observed that myonuclei containing aggregates are larger than myonuclei without. When comparing two muscles from the same patient, a similar amount of aggregates is observed in different muscles, except for the pharyngeal muscle where fewer aggregates are observed. This could be due to the peculiar nature of this muscle which has a low level of PAPBN1 and contains regenerating fibers. To confirm the fate of PABPN1 aggregates in a regenerating muscle, we generated a xenograft model by transplanting human OPMD muscle biopsy samples into the hindlimb of an immunodeficient mouse. Xenografts from subjects with OPMD displayed regeneration of human myofibers and PABPN1 aggregates were rapidly present—although to a lower extent-after muscle fiber regeneration. Our data obtained on human OPMD samples add support to the dual non-exclusive models in OPMD combining toxic PABPN1 intranuclear inclusions together with PABPN1 loss of function which altogether result in this late-onset and muscle selective disease.",
keywords = "Human biopsies, Inclusions, Loss of function, Nuclear aggregates, OPMD, PABPN1, Xenograft",
author = "Fanny Roth and Jamila Dhiab and Alexis Boulinguiez and Hadidja-Rose Mouigni and Saskia Lassche and Elisa Negroni and Laura Muraine and Alix Marhic and Alison Oliver and Jeanne Lain{\'e} and Andr{\'e}e Rouche and O{\textquoteright}Ferrall, {Erin K.} and {van Engelen}, Baziel and Coen Ottenheijm and Hagar Greif and Sergiu Blumen and {Lacau St Guily}, Jean and Sophie Perie and Gillian Butler-Browne and Vincent Mouly and Capucine Trollet",
note = "Funding Information: We thank the MYOBANK‐AFM (St{\'e}phane Vasseur and Maud Chapart) of the Institut de Myologie for the access to human muscle samples. The authors would like to thank all patients and control subjects for giving their informed consent for the use of their surgical remnants in this study. We thank Bruno Cadot from the MyoIMAGE facility for imaging support. We thank Anne Bigot for discussions and critical reading of the manuscript. We thank Beno{\^i}t Darqui{\'e} for discussions and help with the myonuclei and aggregate size quantification. The eMyHC antibody (F1.652) used in this study was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at the University of Iowa, Department of Biology, Iowa City, IA. We acknowledge funding from the Association Fran{\c c}aise contre les Myopathies (AFM Telethon), Inserm, Sorbonne Universit{\'e}, Fondation pour la Recherche M{\'e}dicale (FRM; EQUIPE FRM EQU201903007784 and M2R201803006410) and the Fondation Maladies Rares (AP-RM-16-035). This study was also supported by the Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren (grant no. W.OR10-30 to BvE and CO). Funding Information: We thank the MYOBANK‐AFM (St{\'e}phane Vasseur and Maud Chapart) of the Institut de Myologie for the access to human muscle samples. The authors would like to thank all patients and control subjects for giving their informed consent for the use of their surgical remnants in this study. We thank Bruno Cadot from the MyoIMAGE facility for imaging support. We thank Anne Bigot for discussions and critical reading of the manuscript. We thank Beno{\^i}t Darqui{\'e} for discussions and help with the myonuclei and aggregate size quantification. The eMyHC antibody (F1.652) used in this study was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at the University of Iowa, Department of Biology, Iowa City, IA. We acknowledge funding from the Association Fran{\c c}aise contre les Myopathies (AFM Telethon), Inserm, Sorbonne Universit{\'e}, Fondation pour la Recherche M{\'e}dicale (FRM; EQUIPE FRM EQU201903007784 and M2R201803006410) and the Fondation Maladies Rares (AP-RM-16-035). This study was also supported by the Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren (grant no. W.OR10-30 to BvE and CO). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "https://doi.org/10.1007/s00401-022-02503-7",
language = "English",
volume = "144",
pages = "1157--1170",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "6",
}