A novel pathway for transcriptional regulation of alpha-synuclein.
Alpha-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 alpha-synuclein transcription is therefore critical for PD pathogenesis and synaptic function. We previously reported that in PC12 cells and primary neurons, alpha-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 alpha-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 alpha-synuclein transcriptional regulation. Targeting of these pathways may serve to modulate alpha-synuclein so that it achieves desirable levels within neuronal cells.
Clough
R Lee
RL
Division of Basic Neurosciences, Foundation for Biomedical Research of the Academy of Athens (IIBEAA), 11527 Athens, Greece.
Stefanis
Leonidas
L
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007438:Introns / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000873:Anthracenes; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D007093:Imidazoles; D048031:JNK Mitogen-Activated Protein Kinases; D009025:Morpholines; D020932:Nerve Growth Factor; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D051844:alpha-Synuclein; D048051:p38 Mitogen-Activated Protein Kinases; C113580:U 0126; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580