Characterization of mechanisms underlying neuronal survival and plasticity in Huntington's disease

Huntington’s disease is a progressive neurodegenerative disorder caused by the expansion of a CAG tract in the exon-1 of the huntingtin gene. Mutant huntingtin induces a large amount of toxic effects that trigger cell dysfunction and consequently, behavioral alterations such as motor dysfunction, cognitive decline and psychological disturbances. However, before the onset of symptoms individuals are healthy. Thus, it is plausible that compensatory mechanisms may be activated to regulate a balance between cell death and survival. This compensatory mechanism might modulate the progression of Huntington’s disease. Understanding altered mechanisms due to mutant huntingtin expression in order to find new therapeutic targets to reduce neuronal dysfunction/death in Huntington’s disease must be a priority. It is believed that there is a balance between positive signaling for cell survives or dies. Many of the pathways involved in these processes are controlled at the level of phosphorylation and transcription. In this thesis we have studied mechanisms of transcription and protein activation, which are considered one of the main causes that trigger to mutant huntingtin-induced neuronal dysfunction. We have identified two targets, the protein kinase p90Rsk and the transcription factor Elk-1, that are activated during the progression of Huntington’s disease in order to protect striatal cells against mutant huntingtin-induced cell death. These two proteins are tightly related to neuronal survival and transcription regulation. p90Rsk is a kinase that phosphorylates substrates in the cytoplasm inhibiting their pro-apoptotic activity and phosphorylate transcription factors in the nucleus promoting their pro-survival activity. Likewise, Elk-1 promotes the transcription of many immediate early genes related to synaptic plasticity and neuronal survival. We observed an up-regulation of these to proteins during the progression of Huntington’s disease in different mouse models. This up-regulation was necessary to protect striatal cells from mutant-huntingtin. The prevention of cell death is an important point for neurodegenerative diseases; even so, it is unlikely that cellular machinery works well until the death of the cells. In many neurodegenerative diseases, such as Huntington’s disease, neuronal and synaptic dysfunction precedes cell death and occurs long before, or sometimes in absence of cell death. Recent studies suggest that targeting early pathophysiological disturbances in models of Huntignton’s disease can reverse neuronal dysfunction and delay progression to neurodegeneration. In this thesis, we also point out for the first time the modulation of Prostaglandin E2 (PGE2) EP receptors, namely EP1 and EP2, as a therapeutic targets in Huntington’s disease. The activation of EP1 receptor produces an increase in intracellular levels of calcium, while EP2 receptor activation increases cAMP; therefore, the activation of different EP receptors can have opposite effects. Whereas the blockade of EP2-EP4 receptors can aggravate neurodegeneration, antagonizing EP1 receptor has neuroprotective effects. We observed that pharmacological inhibition of EP1 receptor improves motor coordination and reduces memory decline in R6/1mice model of Huntington’s disease. Moreover, EP1 antagonism increases the expression of specific synaptic markers in the striatum and the hippocampus of these mice and also improves the long-term potentiation in the hippocampus. Finally, EP1 receptor antagonism reduces the presence of striatal and hippocampal mutant huntingtin nuclear aggregates in the striatum and the hippocampus of treated-R6/1 mice. Contrary to EP1 receptor, EP2 receptor plays a neuroprotective role in Huntington’s disease. We observe that EP2 receptor activation improves long-term memory in R6/1 mice. Moreover, EP2 activator increases dendritic branching in a BDNF-dependent manner, increases the protein levels of BDNF and the total number of PSD-95+ spines in the hippocampus of these mice. In conclusion, we propose the modulation of PGE2 receptors as a new therapeutic strategy in Huntington’s disease.