P>Alpha-synuclein (SNCA) is a predominantly neuronal protein involved in
the control of neurotransmitter release. The levels of SNCA expression
are closely linked to the pathogenesis of Parkinson’s disease; however,
the biochemical pathways and transcriptional elements that control SNCA
expression are not well understood. We previously used the model system
of neurotrophin-mediated PC12 cell neuronal differentiation to examine
these phenomena. Although these studies were informative, they were
limited to the use of a cell line; therefore, in the current work, we
have turned our attention to cultured primary rat cortical neurons. In
these cultures, SNCA expression increased with time in culture, as the
neurons mature. Luciferase assays based on transient transfections of
fusion constructs encoding components of the transcriptional control
region of SNCA identified various promoter areas that have a positive or
negative effect on SNCA transcription. Intron 1, previously identified
by us as an important regulatory region in the PC12 cell model,
cooperates with regions 5’ to exon 1 to mediate gene transcription.
Using selective pharmacological tools, we find that tyrosine kinase
receptors and the phosphatidyl-inositol 3 kinase signaling pathway are
involved in mediating these effects. The exogenous application of the
neurotrophin brain-derived neurotrophic factor (BDNF) is sufficient on
its own to promote the transcriptional activation of SNCA through this
pathway, but a neutralizing antibody against BDNF failed to affect SNCA
transcription in maturing cultures, suggesting that BDNF is not the main
factor involved in maturation-induced SNCA transcription in this model.
Further in vivo studies are needed to establish the role of neurotrophin
signaling in the control of SNCA transcription