Conditional knockout mice for the Smad-interacting protein and new DNA repair enzyme Tdp2: do embryonic neurogenesis defects contribute to adult neurodegeneration?

Tdp2, a signaling protein discovered in our lab, is also a binding protein for the Parkinson's Disease protein PARKIN7/DJ1. We characterized Tdp2 as a unique DNA repair enzyme relevant to cancer therapy and neurodegeneration. We propose to study Tdp2's role in neurodegeneration based on our preliminary data that Lewy Bodies form in aged Tdp2 knockout mice, which we made. These mutant mice also develop neuroinflammation. We propose to uncouple these two defects by targeting Tdp2 in neuronal cells only, and in embryogenesis. Using targeting in different neuron types and brain regions, we will test the hypothesis if the central nervous system defects and/or neurodegeneration have an embryonic contribution, which may be subtle but relevant. Histology and marker analysis in the mutant brains will be paralleled by RNA-Seq of FACSorted Tdp2-deficient (mid)brain cells. In collaboration, we will analyze the mice at various ages for changes in the dopaminergic, noradrenergic and cholinergic systems, assess mitochondrial and cytoskeleton dependent functions, and phenotype them comprehensively in behavior with respect to motor as well as non-motor (dys)function. This fits in the concept that this research should be directed not only towards the symptomatic phase of the disease but also towards the pre-motoric phase in order to contribute to the development of biomarkers and/or prevention of the onset of neurodegenerative disease.