title: Overexpression of ALS-associated p.M337V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice.
abstract: Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis (ALS), while wild-type TDP-43 is a pathological hallmark of patients with sporadic ALS and frontotemporal lobar degeneration (FTLD). Various in vitro and in vivo studies have also demonstrated toxicity of both mutant and wild-type TDP-43 to neuronal cells. To study the potential additional toxicity incurred by mutant TDP-43 in vivo, we generated mutant human TDP-43 (p.M337V) transgenic mouse lines driven by the Thy-1.2 promoter (Mt-TAR) and compared them in the same experimental setting to the disease phenotype observed in wild-type TDP-43 transgenic lines (Wt-TAR) expressing comparable TDP-43 levels. Overexpression of mutant TDP-43 leads to a worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology. Furthermore, we show that cellular aggregate formation or accumulation of TDP-43 C-terminal fragments (CTFs) are not primarily responsible for development of the observed disease phenotype in both mutant and wild-type TDP-43 mice.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610, Antwerp, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Janssens
authors.forename: Hans
authors.initials: H
authors.lastname: Wils
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.forename: Geert
authors.initials: G
authors.lastname: Joris
authors.forename: Ivy
authors.initials: I
authors.lastname: Cuijt
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick-de Groote
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D004804:Eosinophils / Q000378:metabolism / Q000648:ultrastructure; D005911:Gliosis / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure; D019076:Transgenes / Q000235:genetics; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D057149:Ubiquitinated Proteins