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: Antonella Caccamo, Smita Majumder, Salvatore Oddo
• Journal: The American journal of pathology (Am J Pathol) Vol. 180 Issue 1 Pg. 293-302 (Jan 2012) ISSN: 1525-2191 [Electronic] United States
• PMID: 22067910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins

Topics

• Animals
• Cognition Disorders (etiology, metabolism)
• DNA-Binding Proteins (metabolism)
• Executive Function (physiology)
• Frontotemporal Lobar Degeneration (metabolism, psychology)
• Maze Learning
• Mice
• Mice, Transgenic
• Recognition, Psychology (physiology)
• TDP-43 Proteinopathies (metabolism, psychology)