title: Nuclear protein spreading: implication for pathophysiology of neuromuscular diseases.
abstract: While transfer of a protein encoded by a single nucleus to nearby nuclei in multinucleated cells has been known for almost 25 years, the biological consequences for gain-of-function diseases have not been considered. Here, we have investigated nuclear protein spreading and its potential consequences in two of the three most prevalent neuromuscular diseases. By performing co-cultures between diseased or control human myoblasts and murine C2C12 myoblasts, we demonstrate that in facioscapulohumeral dystrophy, although the transcription of the toxic protein DUX4 occurs in only a limited number of nuclei, the resulting protein diffuses into nearby nuclei within the myotubes, thus spreading aberrant gene expression. In myotonic dystrophy type 1, we observed that in human-mouse heterokaryons, the expression of a mutated DMPK from human nuclei titrates splicing factors produced by neighboring nuclei, inducing the mis-splicing of several pre-mRNAs in murine nuclei. In both cases, the spreading of the pathological phenotypes from one nucleus to another is observed, highlighting an additional mechanism that contributes to the dissemination and worsening of the muscle pathogenesis. These results indicate that nuclear protein spreading may be an important component of pathophysiology of gain of function muscular diseases which should be taken into consideration in the design of new therapeutic approaches.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, F-75013 Paris, France, INSERM UMRS974, F-75013 Paris, France, CNRS FRE 3617, F-75013 Paris, France and Institut de Myologie, F-75013 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Ferreboeuf
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, F-75013 Paris, France, INSERM UMRS974, F-75013 Paris, France, CNRS FRE 3617, F-75013 Paris, France and Institut de Myologie, F-75013 Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, F-75013 Paris, France, INSERM UMRS974, F-75013 Paris, France, CNRS FRE 3617, F-75013 Paris, France and Institut de Myologie, F-75013 Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, F-75013 Paris, France, INSERM UMRS974, F-75013 Paris, France, CNRS FRE 3617, F-75013 Paris, France and Institut de Myologie, F-75013 Paris, France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, F-75013 Paris, France, INSERM UMRS974, F-75013 Paris, France, CNRS FRE 3617, F-75013 Paris, France and Institut de Myologie, F-75013 Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, F-75013 Paris, France, INSERM UMRS974, F-75013 Paris, France, CNRS FRE 3617, F-75013 Paris, France and Institut de Myologie, F-75013 Paris, France julie.dumonceaux@upmc.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D065636:Myotonin-Protein Kinase / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D012326:RNA Splicing; D014158:Transcription, Genetic
chemical_list: C585517:DMPK protein, human; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D065636:Myotonin-Protein Kinase