| Ubiquitin-positive neuronal inclusions comprised of TAR DNA binding protein of 43-kDA (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). TDP-43 is a DNA/RNA binding protein that is involved in widespread mRNA metabolism and plays a critical, although undefined, role in development. In this thesis, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain, called iTDP-43 WT, to better understand the normal biological functions of TDP-43 as well as its role in disease. Continuous TDP-43 expression during early neuronal development produced a complex phenotype including aggregation of phosphorylated TDP-43 (pTDP-43), increased ubiquitin immunoreactivity, mitochondrial abnormalities, non-progressive neurodegeneration, and early lethality. The window of TDP-43-mediated neurotoxicity occurs in the third postnatal week when synaptic maturation and synaptic pruning is ongoing, but the mechanism remains to be determined. hTDP-43 suppression during adulthood moderately ameliorated features of the developmental phenotype including a decrease in pTDP-43 inclusions, ubiquitin, and gliosis. Furthermore, spatial memory was improved without an increase neuronal number. hTDP-43 induction in the more mature forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, pTDP-43 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 strategy of adult hTDP-43 induction provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies. |
