title: Cognitive decline typical of frontotemporal lobar degeneration in transgenic mice expressing the 25-kDa C-terminal fragment of TDP-43.
abstract: Transactive response DNA-binding protein 43 (TDP-43) is the pathological signature protein in several neurodegenerative disorders, including the majority of frontotemporal lobar degeneration cases (FTLD-TDP), motor neuron disease, and amyotrophic lateral sclerosis. Pathological TDP-43 is mislocalized from its nuclear location to the cytoplasm, where it accumulates and is proteolytically cleaved to form C-terminal fragments. Although the 25-kDa C-terminal fragment of TDP-43 (TDP-25) accumulates in affected brain regions, its role in the disease pathogenesis remains elusive. To address this problem, we have generated a novel transgenic mouse that selectively expresses TDP-25 in neurons. We show that transgenic mice expressing TDP-25 develop cognitive deficits associated with the build-up of soluble TDP-25. These cognitive deficits are independent of TDP-43-positive inclusions and occur without overt neurodegeneration. Additionally, we show that the expression of TDP-25 is sufficient to alter the processing of endogenous full-length TDP-43. These studies represent the first in vivo demonstration of a pathological role for TDP-25 and strongly suggest that the onset of cognitive deficits in TDP-43 proteinopathies is independent of TDP-43 inclusions. These data provide a framework for understanding the molecular mechanisms underlying the onset of cognitive deficits in FTLD-TDP and other TDP-43 proteinopathies; thus, the TDP-25 transgenic mice represent a unique tool to reach this goal.
authors: Department of Physiology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
authors: Antonella
authors: A
authors: Caccamo
authors: Smita
authors: S
authors: Majumder
authors: Salvatore
authors: S
authors: Oddo
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056344:Executive Function / Q000502:physiology; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism / Q000523:psychology*; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D021641:Recognition, Psychology / Q000502:physiology; D057177:TDP-43 Proteinopathies / Q000378:metabolism / Q000523:psychology*
chemical_list: D004268:DNA-Binding Proteins