-Synuclein is an abundant neuronal protein that has been linked to both normal synaptic function and neurodegeneration--in particular, Parkinson’s disease (PD). Uncovering mechanisms that control -synuclein transcription is therefore critical for PD pathogenesis and synaptic function. We previously reported that in PC12 cells and primary neurons, -synuclein is transcriptionally up-regulated after application of growth factors. In the current work we have characterized the pathway involved in this regulation in PC12 cells. The MAP/ERK pathway, and in particular Ras, is both sufficient and necessary for the NGF and basic fibroblast growth factor (bFGF) -mediated response. Significantly, response elements for this pathway, including a putative occult promoter, lie within intron 1, a hitherto unappreciated regulatory region of the gene that may be utilized in this or other settings. The PI3 kinase pathway is also involved in -synuclein regulation, but response elements for this pathway appear to lie primarily outside of intron 1. These findings indicate that NGF- and bFGF-mediated signal transduction via the MAP/ERK and PI3 kinase pathways, and in part via regulatory regions within intron 1, may be involved in -synuclein transcriptional regulation. Targeting of these pathways may serve to modulate -synuclein so that it achieves desirable levels within neuronal cells.--Clough, R. L., Stefanis, L. A novel pathway for transcriptional regulation of -synuclein.