Changes in the expression of the striatal-enriched protein tyrosine phosphatase and of extracellular regulated kinase in the R6/2 mouse model of Huntington's disease

Objective: As neuroprotection achieved by the increase CREB and BDNF involves the activation of ERK pathway (Yao et al, 2009), we studied changes in the expression of pERK and STEP in WT and R6/2 mice treated with rolipram. Background: The mitogen-activated protein kinases (MAPKs superfamily comprises three major signaling pathways: the extracellular signal-regulated protein kinases (ERKs), the c-Jun N-terminal kinases or stress- activated protein kinases (JNKs/SAPKs) and the p38 family of kinases. ERK signaling has been implicated in a number of neurodegenerative disorders, including Huntington’s disease (HD). Phosphorylation patterns of ERK and JNK are altered in cell models of HD. In this study, we aimed at studying the correlations between ERK and the neuronal vulnerability to HD degeneration in the R6/2 transgenic mouse model of HD. Methods: The study groups included rolipram-treated and salinetreated wild-type and R6/2 mice. Immunohistochemistry for phospho-ERK (p-ERK, the activated form of ERK) and dual label immunofluorescence for p-ERK and each of the striatal neuronal markers were employed on perfusion-fixed brain sections from R6/2 and wild-type mice. Results: Our study shows that striatal neurons, both spiny projection and interneurons, are completely devoid of p-ERK immunoreactivity in the wild-type mouse. Conversely, parvalbumin-labeled GABAergic interneurons of the striatum are highly enriched in pERK in the R6/2 mice, cholinergic and somatostatinergic interneurons are devoid of it. Interestingly, the parvalbuminergic interneuron subpopulation of the striatum is the only interneuron subset that is extremely prone to degenerate in HD. Conclusions: Our study confirms and extends the concept that the expression of phosphorilated ERK is related to neuronal vulnerability and is implicated in the pathophysiology of cell death in HD.