Maki Omura, Katia (2014) Identification of new molecular targets involved in pathogenesis of Parkinson’s Disease: new perspectives for therapeutic intervention. [Tesi di dottorato]

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Abstract

The hypothesis that an alteration of intracellular calcium concentrations ([Ca2+]i) might participate to the selective degeneration of SNpc neurons has been recently demonstrated thus suggesting that an alteration of [Ca2+]i homeostasis could be also involved in the pathogenesis of PD (Schmitz et al. 2007). In this scenario, the Na+-Ca2+ exchanger (NCX), the major Ca2+ extruding and influx system in the cells, may play a relevant role since it works, together with other plasma membrane and sarco-endoplasmatic pumps, to maintain [Ca2+]i homeostasis. Preliminary results obtained in our laboratory demonstrated that, among the three NCX isoforms, NCX3, highly expressed in the brain, plays a pivotal role in the maintenance of intracellular Na+ and Ca2+ homeostasis during cerebral ischemia, and that the deletion of the ncx3 gene in mice has detrimental consequences on basal synaptic transmission, LTP regulation, spatial learning, and memory performance. In the present study, we investigated whether alterations in the expression of NCX isoforms might be correlated with dopaminergic neuronal loss observed in mice expressing human A53T variant of alpha-synuclein during their life span. We found that in the midbrain the expression of NCX2 and NCX3 isoforms is reduced during aging in A53T mice compared to wild type mice that is correlated with a reduce in tyrosine hydroxylase expression , whereas an increase in NCX1 expression was found in 10 months A53T old mice in striatum. Interestingly, in A53T dopaminergic neurons it is observed a decrease in NCX3 expression that corresponds to an increase in cytosolic calcium concentrations and also mitochondrial contents. In conclusion, the results reported in the present study let to hypothesize that the changes in NCXs expression occurring in midbrain and in striatum of A53T mice correlates with loss of dopaminergic neurons probably due to an imbalance of the mechanisms involved in the regulation of intracellular calcium homeostasis. These findings reveal new potential targets useful to develop alternative strategies to treat Parkinson’s disease.

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