Several studies revealed that both PDE10A, the cAMP/cGMP hydrolyzing enzyme highly enriched in mammalian striatum, and many proteins involved in synaptic transmission including cAMP/PKA transducing receptors, are post-translationally modified through S-palmitoylation. The altered expression of PDE10A and D2 receptor, previously demonstrated in dystonia animal models, could depend on a common modification of lipid post-translational modification that cause a dynamic relocation among different cellular compartments. Therefore, the aim of this project is to study the expression of PDE10A, adenosine (A2A) and dopaminergic (D1 and D2) receptors, that are involved in the synaptic transduction pathways mediated by cyclic nucleotides in the basal ganglia, in the dystonia Tor1a delta gag/+ mouse model. The experimental approach will include immunohistochemistry, confocal microscopy, biochemistry, physiology and the investigation of post-translational S-palmitoyl modification.
Dystonia pathophysiology has been partly linked to downregulation and dysfunction of many receptor associated to signalling transduction pathways of well-known neurotransmitters in particular dopamine receptors. Many evidences support the hypothesis that the greatest alteration depends on the decrease in function and expression of the dopamine D2 receptor in striatum. As dystonic animal model we have already utilized mice overexpressing the human wild type (hWT) or mutant (hMT) torsinA (Sharma et al., 2005). In this model, we found an opposite regulation of PDE10A in both striatal output pathways, with increased expression and enzymatic activity in striatopallidal pathway, and decreased in the striatoentopeduncular one. This differential expression could mirror the altered trafficking and accumulation of PDE10A in presynaptic region of the dystonic synapses probably due to an altered post-traslational modification such as palmitoilatyon that occurs in this enzyme. This post-translational modification occurs also in dopaminergic receptors modifying its functionality and expression.
We aimed to investigate the possible morpho-structural correlates of D2 receptor in the striatum of a DYT1 mouse model and we will try to prove that all these alterations depend on an altered lipid post-translational modification process that could be the main etiologic agent of dystonia.
References
Sharma et al., (2005) J Neurosci 25:5351-5355