The long-term objective of this project is the development of genetic approaches to treat neurodegenerative diseases. One of the strategies pursued by the Unit is the discovery of molecules that alter the expression of relevant endogenous genes within the brain. Thus, current efforts focus on obtaining detailed insight into the transcription control of genes relevant to Parkinson's disease. During FY97 we focused on the dopamine receptors expressed in the striatum. We had found that the human D1A dopamine receptor gene is transcribed from two promoters, one located upstream of exon 1 and another located within the single intron of this gene. In brain, both promoters are active while in kidney the upstream promoter is inactive resulting in the generation of only short D1A transcripts lacking exon 1 driven from the intron promoter. We now discovered that lack of activity of the upstream promoter in kidney cells is due to absence of the nuclear protein complex that actives the upstream promoter in brain. We also found that Brn-4, a member of the POU family of transcription factors activates the D1A gene while other members could compete with and repress the activity of Brn-4 on this gene. We had also found that the D2 dopamine receptor is under strong negative modulatory control residing in a stretch of sequence that includes two Sp1 consensus sequences. We found that the latter bind to Sp1 and to Sp3. Finally, in the process of cloning transcription factors that bind to Sp1 consensus sequences, we isolated a novel zinc finger protein that is highly expressed in the adult and developing brain and is induced by the potent neurotrophic factor glial cell-derived neurotrophic factor.