The neurotrophic factors (NTF), BDNF and GDNF, have been proposed as potential gene therapeutic agents for Parkinson's disease (PD) to both slow degeneration and increase neuronal function of substantia nigra dopamine (SN-DA) neurons. To evaluate the NTF as rational therapeutic agents for PD, it is crucial to understand the functional roles and mechanisms of action of each NTF on SN-DA cells in both normal- and patho-physiological conditions. Previously used model systems for the evaluation of NTF have suffered from both paucity of DA cells in heterogeneous fetal mesencephalic cultures and the inaccessibility of SN-DA neurons for genetic manipulation in either normal or Parkinson's animal models. Therefore, as a crucial first step in the elucidation of the functional and regulatory roles of the exogenous NTF, we have developed both (1) SN-DA neuronal cell lines and (2) transgenic mouse models with an on-off genetic switch to control the levels of NTF production in SN-DA neurons. In the current proposal the newly developed SN-DA cell lines and transgenic mouse models will be utilized to provide a basic biological rationale for the use of NTF in PD and fetal grafts. [The] current proposal tests the hypothesis that the exogenous NTF differentially promotes DA neuronal survival, DA phenotypic differentiation, and protection against MPTP via direct and/or indirect mechanisms depending on the developmental states of SN-DA neurons.
Specific Aim 1 will address the differential mechanism[s] of neurotrophic and neuroprotective actions of BDNF and GDNF in our SN-DA cells, together with mesencephalic astrocyte coculture system. In complementary studies, Specific Aim 2 will examine the in vivo functional effects of controlled over-expression of BDNF and GDNF on SN-DA neurons during development, aging and in an animal model of PD. The proposed studies will provide both new insights into SN-DA neuronal degeneration during normal aging and PD. The proposed studies will provide both new insights into SN-DA neuronal degeneration during normal aging and PD as well as the biological rationale for gene therapy and SN-DA neuron transplantation in Parkinson""""""""s patients.
