title: Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction.
abstract: Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Baoli
authors.initials: B
authors.lastname: Yang
authors.forename: Joshua
authors.initials: J
authors.lastname: Knight
authors.forename: Ian M
authors.initials: IM
authors.lastname: Farnham
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Wuertzer
authors.forename: Simon
authors.initials: S
authors.lastname: D'Alton
authors.forename: Wen-lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.forename: Linda
authors.initials: L
authors.lastname: Rousseau
authors.forename: Brittany
authors.initials: B
authors.lastname: Scott
authors.forename: Michael
authors.initials: M
authors.lastname: Jurasic
authors.forename: John
authors.initials: J
authors.lastname: Howard
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Rachel
authors.initials: R
authors.lastname: Bailey
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sarkisian
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D025801:Ubiquitin