title: Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS.
abstract: The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.|Motor Neuron Disease Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Yazi D
authors.initials: YD
authors.lastname: Ke
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.|Motor Neuron Disease Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Annika
authors.initials: A
authors.lastname: van Hummel
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Stevens
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Amadeus
authors.initials: A
authors.lastname: Gladbach
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ippati
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Mian
authors.initials: M
authors.lastname: Bi
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Wei S
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Krüger
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: van der Hoven
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Volkerling
authors.affiliation: Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Andre
authors.initials: A
authors.lastname: Bongers
authors.affiliation: Neuroscience Research Australia, Sydney, NSW, 2036, Australia.
authors.forename: Glenda
authors.initials: G
authors.lastname: Halliday
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, 4102, Australia.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.affiliation: Brain and Mind Research Institute, Faculty of Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW, 2050, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kiernan
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia.|Transgenic Animal Unit, Mark Wainwright Analytical Centre, UNSW Australia, Sydney, NSW, 2052, Australia.
authors.forename: Fabien
authors.initials: F
authors.lastname: Delerue
authors.affiliation: Dementia Research Unit, Department of Anatomy, Faculty of Medicine, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia. l.ittner@unsw.edu.au.|Neuroscience Research Australia, Sydney, NSW, 2036, Australia. l.ittner@unsw.edu.au.|Transgenic Animal Unit, Mark Wainwright Analytical Centre, UNSW Australia, Sydney, NSW, 2052, Australia. l.ittner@unsw.edu.au.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004318:Doxycycline; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020127:Recovery of Function / Q000502:physiology*; D065852:Spatial Memory / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D004318:Doxycycline
keywords: Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; Mouse model; Pathogenic mutation; TDP-43