PROJECT 2. ENHANCING FUNCTION OF GRAFTED PRIMATE DOPAMINE NEURONS WITH NEUROTROPHIC FACTORS The death of the vast majority of transplanted dopamine neurons within the first few days appears to limit the success of this treatment strategy for Parkinson's disease. The inadequacy of critical growth factors in the adult parkinsonian brain may be a major cause of early cell death and restricted outgrowth of grafts placed into the striatum. This project proposes studies to determine whether chronically delivered neurotrophic factors can increase the survival and outgrowth of fetal mesencephatic dopamine neurons, and improve the biochemical and functional outcome of neural grafting in parkinsonian primates. Factors tested will include glial cell line-derived neurotrophic factor (GDNF), delivered biologically by macroencapsulated cells. Fetal striatum releases several neurotrophic factors besides GDNF, and this milieu provides critical support to dopamine neurons during their normal development. Thus, the effect of factors released from fetal striatum enriched in oligodendrocyte-type-2 astrocyte (SO2A) progenitor cells will also be investigated on dopamine neuron survival. Experiments will utilize implantation of GDNF-releasing capsules, or cografting of SO2A cells at increasing distances from ventral mesencephalic grafts placed into the caudate in the MPTP-treated monkey, a model that reproduces all the hallmark behavioral features of Parkinson's disease. Defined dissections of donor tissue and pre-selection of MPTP-treated monkeys will limit variability in the studies. The main end-point measures will be improvement in parkinsonism, correlated with dopamine neuron survival and soma size, and dopamine fiber outgrowth, determined by biochemical measures and light and electron microscopy. Methods for these studies are in place, and key pilot studies strongly support feasibility and the hypotheses. These studies will increase understanding of the interaction of primate fetal dopamine neurons with neurotrophic factors, and will lead to improved and more reproducible methods of cellular replacement which may benefit patients with Parkinson's disease and possibly other neurodegenerative disorders.
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