| First Author | Caccamo A | Year | 2012 |
| Journal | Am J Pathol | Volume | 180 |
| Issue | 1 | Pages | 293-302 |
| PubMed ID | 22067910 | Mgi Jnum | J:180165 |
| Mgi Id | MGI:5305542 | Doi | 10.1016/j.ajpath.2011.09.022 |
| Citation | Caccamo A, et al. (2012) Cognitive decline typical of frontotemporal lobar degeneration in transgenic mice expressing the 25-kDa C-terminal fragment of TDP-43. Am J Pathol 180(1):293-302 |
| abstractText | 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. |
