Investigation of the antiapopototic effects of Dopamine Neuron Stimulating Peptide-11

SPECIFIC AIMS Neurotrophic growth factors are a class of structurally and functionally related proteins that play a key role in neuron formation during development and after injury (lbanez, 1998). Because of their native cellular function, neurotrophic factors have received considerable attention as potential therapeutic agents for brain disorders, including Parkinson's disease (PD). Despite the long- established trophic effects of the mature growth factor, recent studies have revealed that the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) proprotein binds to a novel class of receptors and promotes apoptosis. Due to the conservation of structure and function within the neurotrophic growth factor family, this suggests that other prosequences within this family may have additional functions and understanding the molecular and cellular functions of these sequences could pave the way for therapies targeting aging or age-related neurodegenerative diseases. While the cellular function of the mature, processed glial cell-line derived growth factor (GDNF) protein is known to produce significant beneficial effects to dopaminergic neurons, the role of the highly conserved proprotein sequence is not well-understood. Examination of the GDNF prosequence predicts internal dibasic endopeptidase sites that would yield smaller amidated peptides, named Dopamine Neuron Stimulating Peptides (DNSP), upon proteolytic processing. Preliminary evaluation of these propeptides has determined that the eleven amino acid residue fragment, DNSP-1 1, exhibits trophic-like responses in young Fischer 344 (F344) rats. The research outlined in the current proposal is based on our hypothesis that the DNSP-1 1 is the functional portion of the GDNF prosequence; and that this peptide functions its neurobiological effects by suppressing apoptotic pathways. The goal of the proposed work is to decipher the molecular and cellular mechanism of DNSP- 11. Results from this study will serve three functions: 1) to validate the DNSP-11 molecule for its trophic role and establish an assay to validate additional novel candidates, 2) serve as a foundation for future translational Parkinson's disease (PD) rat and nonhuman primate studies, and 3) to develop our understanding that trophic functions exist within the neurotrophic factor family of prosequences.