Our recent work showed, in the basal ganglia circuit of a transgenic DYT1 mouse model, an altered expression of the enzyme phosphodiesterase 10A (PDE10A). PDE10A is highly enriched in mammalian striatum, specifically in the GABAergic medium spiny neurons, and reaches the output structures of basal ganglia through the axonal transport along the projections of these striatal neurons. Moreover, several studies revealed that PDE10A and many proteins, involved in synaptic transmission, 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.
In our previous work (D'Angelo et al., 2017), we utilized mice overexpressed human wild type (hWT) or mutant (hMT) torsinA (Sharma et al., 2005). In this model, we found a differential, opposite regulation of PDE10A in the 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. In Tor1a delta gag/+ mice we observed a similar imbalance 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
D'Angelo et al., (2017) J Neurosci 37(8):2112-2124
Sharma et al., (2005) J Neurosci 25:5351-5355