title: A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia.
abstract: Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size of motor endplates and by a decrease of sciatic nerve axons area. However, spinal motor neurons cell bodies were preserved until death. In addition to the motor dysfunctions, CHMP2Bintron5mice progressively developed FTD-relevant behavioural modifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2Bintron5As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis and microgliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2Bintron5in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Vernay
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Therreau
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Université Joseph Fourier, F-38700 La Tronche, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Blot
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, UMR5239 CNRS/ENS Lyon/UCBL/HCL Ecole normale supérieure de Lyon, F-69364 Lyon Cedex 07, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Risson
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dirrig-Grosch
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Waegaert
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Thiebault
authors.initials: T
authors.lastname: Lequeu
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Neurology department, Hôpitaux civils and CMRR, F-68000 Colmar, France.
authors.forename: François
authors.initials: F
authors.lastname: Sellal
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, UMR5239 CNRS/ENS Lyon/UCBL/HCL Ecole normale supérieure de Lyon, F-69364 Lyon Cedex 07, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Université Joseph Fourier, F-38700 La Tronche, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Sadoul
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.affiliation: INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France frederique.rene@unistra.fr.|Université de Strasbourg, UMRS1118, Faculté de Médecine, Fédération de Médecine Translationelle de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000096:biosynthesis* / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: C503812:CHMP2B protein, human; C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins