Project I of this Program Project Grant seeks to study the neurodegeneration associated with SV40 T antigen expression in Purkinje precursor cells and neurons. Using regulatory DNA elements from a Purkinje cell-specific gene, Pcp-2, transgenic mice have been established that express SV40 T antigen in their cerebellar Purkinje cells. Embryonic expression of SV40 in one line, SV5, results in an arrest of cerebellar development. In two other lines, SV4 and SV6, transgene expression initiates in Purkinje neurons after their migration to and maturation in the cerebellar cortex. In these lines, SV40 T antigen induces Purkinje cell degeneration. A series of experiments are proposed to characterize the molecular basis of the induction of Purkinje cell death by SV40 T antigen. In addition, neuropathological studies will be performed on these transgenic lines to further characterize the effects of Purkinje cell death. The goals are to understand the molecular basis of this neurodegeneration and to assess whether these genetic models will provide insights into neurodegenerative diseases in general.
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