A novel pathway for transcriptional regulation of α‐synuclein

α‐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, α‐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 α‐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 α‐synuclein transcriptional regulation. Targeting of these pathways may serve to modulate α‐synuclein so that it achieves desirable levels within neuronal cells.—Clough, R. L., Stefanis, L. A novel pathway for transcriptional regulation of α‐synuclein. FASEB J. 21, 596–607 (2007)