title: Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments.
abstract: Transactive response DNA-binding protein 43 ubiquitinated inclusions are a hallmark of amyotrophic lateral sclerosis and of frontotemporal lobar degeneration with ubiquitin-positive inclusions. Yet, mutations in TARDBP, the gene encoding these inclusions are associated with only 3% of sporadic and familial amyotrophic lateral sclerosis. Recent transgenic mouse studies have revealed a high degree of toxicity due to transactive response DNA-binding protein 43 proteins when overexpressed under the control of strong neuronal gene promoters, resulting in early paralysis and death, but without the presence of amyotrophic lateral sclerosis-like ubiquitinated transactive response DNA-binding protein 43-positive inclusions. To better mimic human amyotrophic lateral sclerosis, we generated transgenic mice that exhibit moderate and ubiquitous expression of transactive response DNA-binding protein 43 species using genomic fragments that encode wild-type human transactive response DNA-binding protein 43 or familial amyotrophic lateral sclerosis-linked mutant transactive response DNA-binding protein 43 (G348C) and (A315T). These novel transgenic mice develop many age-related pathological and biochemical changes reminiscent of human amyotrophic lateral sclerosis including ubiquitinated transactive response DNA-binding protein 43-positive inclusions, transactive response DNA-binding protein 43 cleavage fragments, intermediate filament abnormalities, axonopathy and neuroinflammation. All three transgenic mouse models (wild-type, G348C and A315T) exhibited impaired learning and memory capabilities during ageing, as well as motor dysfunction. Real-time imaging with the use of biophotonic transactive response DNA-binding protein 43 transgenic mice carrying a glial fibrillary acidic protein-luciferase reporter revealed that the behavioural defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in amyotrophic lateral sclerosis pathogenesis. These novel transactive response DNA-binding protein 43 transgenic mice mimic several characteristics of human amyotrophic lateral sclerosis-frontotemporal lobar degeneration and they should provide valuable animal models for testing therapeutic approaches.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Boulevard Laurier, Quebec, QC G1V 4G2, Canada.
authors.forename: Vivek
authors.initials: V
authors.lastname: Swarup
authors.forename: Daniel
authors.initials: D
authors.lastname: Phaneuf
authors.forename: Christine
authors.initials: C
authors.lastname: Bareil
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000648:ultrastructure; D001522:Behavior, Animal / Q000502:physiology; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D018782:Maze Learning; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009483:Neuropsychological Tests; D064531:Peripherins; D045442:Rotarod Performance Test
chemical_list: D004268:DNA-Binding Proteins; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D064531:Peripherins