α-Synuclein expression is induced by depolarization and cyclic AMP in enteric neurons

Accumulated evidence emphasizes the importance of α-synuclein expression levels in Parkinson's disease (PD) pathogenesis. PD is a multicentric disorder that affects the enteric nervous system (ENS), whose involvement may herald the degenerative process in the CNS. We therefore undertook the present study to investigate the mechanisms involved in the regulation of expression of α-synuclein in the ENS. The regulation of α-synuclein expression was assessed by qPCR and western blot analysis in rat primary culture of ENS treated with KCl and forskolin. A pharmacological approach was used to decipher the signaling pathways involved. Intraperitoneal injections of Bay K-8644 and forskolin were performed in mice, whose proximal colons were further analyzed for α-synuclein expression. Depolarization and forskolin increased α-synuclein mRNA and protein expression in primary cultures of ENS, although L-type calcium channel and protein kinase A, respectively. Both stimuli increased α-synuclein expression through a Ras/extracellular signal-regulated kinases pathway. An increase in α-synuclein expression was also observed in vivo in the ENS of mice injected with Bay K-8644 or forskolin. In conclusion, we have identified stimuli leading to α-synuclein over-expression in the ENS, which could be critical in the initiation of the pathological process in PD.