Alpha-synuclein (SNCA)
protein aggregation plays a causal role in
Parkinson's disease (PD). The SNCA
protein modulates neurotransmission via the
SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic
dopamine deficit is alleviated by treatment with
levodopa (
L-DOPA), but postsynaptic
plastic changes induced by this treatment lead to a development of
involuntary movements (
dyskinesia). While this process is currently modeled in rodents harboring
neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of
dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with
prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with
apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of
apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of
extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos
messenger RNA (
mRNA), were examined in striatal tissue at 30 and 100 min after
apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6
mRNA (two
MAPK phosphatases). At the same time point, Fos
mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after
apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6
mRNA was significantly larger in mutant mice than wild-type controls. At this time point,
apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with
apomorphine-induced
involuntary movements in a genetic mouse model of
synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal
dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD.