title: Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons. Mutations in the gene encoding the nuclear matrix protein Matrin 3 have been found in familial cases of ALS, as well as autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We previously found that spinal cord and muscle, organs involved in either ALS or distal myopathy, have relatively lower levels of Matrin 3 compared to the brain and other peripheral organs in the murine system. This suggests that these organs may be vulnerable to any changes in Matrin 3. In order to determine the role of Matrin 3 in these diseases, we created a transgenic mouse model for human wild-type Matrin 3 using the mouse prion promoter (MoPrP) on a FVB background.We identified three founder transgenic lines that produced offspring in which mice developed either hindlimb paresis or paralysis with hindlimb and forelimb muscle atrophy. Muscles of affected mice showed a striking increase in nuclear Matrin 3, as well as the presence of rounded fibers, vacuoles, nuclear chains, and subsarcolemmal nuclei. Immunoblot analysis of the gastrocnemius muscle from phenotypic mice showed increased levels of Matrin 3 products migrating at approximately 120 (doublet), 90, 70, and 55 kDa. While there was no significant change in the levels of Matrin 3 in the spinal cord in the phenotypic mice, the ventral horn contained individual cells with cytoplasmic redistribution of Matrin 3, as well as gliosis. The phenotypes of these mice indicate that dysregulation of Matrin 3 levels is deleterious to neuromuscular function.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Moloney
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Rayaprolu
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Howard
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fromholt
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Hilda
authors.initials: H
authors.lastname: Brown
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Collins
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Mariela
authors.initials: M
authors.lastname: Cabrera
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Duffy
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Siemienski
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL, USA.
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|Department of Neuroscience, University of Florida, Gainesville, FL, USA.|McKnight Brain Institute, Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA. drb1@ufl.edu.|Department of Neuroscience, University of Florida, Gainesville, FL, USA. drb1@ufl.edu.|McKnight Brain Institute, Department of Neuroscience, University of Florida, Gainesville, FL, USA. drb1@ufl.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA. jada.lewis@ufl.edu.|Department of Neuroscience, University of Florida, Gainesville, FL, USA. jada.lewis@ufl.edu.|McKnight Brain Institute, Department of Neuroscience, University of Florida, Gainesville, FL, USA. jada.lewis@ufl.edu.
authors.forename: Jada
authors.identifier: 0000-0003-0004-6597
authors.initials: J
authors.lastname: Lewis
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D049310:Distal Myopathies / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010291:Paresis / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: C518587:MATR3 protein, human; D034521:Nuclear Matrix-Associated Proteins; D016601:RNA-Binding Proteins
keywords: ALS; Distal myopathy; Matrin 3; Transgenic mouse model