title: Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43.
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) are two neurodegenerative disorders characterized by the accumulation of TDP-43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FTLD-TDP and ALS; however, little is known about its role in disease pathogenesis. We have previously developed transgenic mice overexpressing low levels of TDP-25 (TgTDP-25(+/0)), which at 6 months of age show mild cognitive impairments and no motor deficits. To better understand the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP, we generated TDP-25 homozygous mice (TgTDP-25(+/+)), thereby further increasing TDP-25 expression. We found a gene-dosage effect on cognitive and motor function at 15 months of age, as the TgTDP-25(+/+) showed more severe spatial and working memory deficits as well as worse motor performance than TgTDP-25(+/0) mice. These behavioral deficits were associated with increased soluble levels of TDP-25 in the nucleus and cytosol. Notably, high TDP-25 levels were also linked to reduced autophagy induction and proteasome function, two events that have been associated with both ALS and FTLD-TDP. In summary, we present strong in vivo evidence that high levels of TDP-25 are sufficient to cause behavioral deficits and reduce function of two of the major protein turnover systems: autophagy and proteasome. These mice represent a new tool to study the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP.
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ 85351, USA, Department of Biological, Geological and Environmental Sciences, University of Catania, Catania 95125, Italy and.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caccamo
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ 85351, USA.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Shaw
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Catania, Catania 95125, Italy and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guarino
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Catania, Catania 95125, Italy and.
authors.forename: Angela
authors.initials: A
authors.lastname: Messina
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ 85351, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Walker
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ 85351, USA, Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA oddo@email.arizona.edu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001522:Behavior, Animal; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D046988:Proteasome Endopeptidase Complex