Plasma membrane Ca2+ Atpase 1 as a candidate to mediate the degeneration of dopaminergic neurons by inflammation in Parkinson?s disease

ERHARDT, BRENDA; CASABONA, JUAN C.; PABLO ALEJANDRO BOCHICCHIO; CAVALIERE CANDEDO VERÓNICA; ALLO MIGUEL; CASTAÑO EDUARDO; MARCORA, MARIA SILVINA; TARELLI RODOLFO; DIEGO HERNÁN BODIN; MARIA ISABEL FARIAS; HÖCHT CHRISTIAN; LEAL MARIA CELESTE; DE LELLA EZCURRA ANA; FRENKEL LIA; SILVA, BERENICE ANABEL; CARINA CINTIA FERRARI; CHERNOMORETZ ARIEL; FERNANDO JUAN PITOSSI

Niza

Congreso; International Congress of Parkinson disease and Movement disorders; 2019

Objective: To identify genes involved in the degeneration of the dopaminergicneurons (DN) of the substantia nigra (SN) by inflammation.Background: Parkinson?s disease (PD) is characterized by a progressivedeath of DN within the SN. The molecular basis of the DN degenerationare unknown. DN show a peculiar pacemaker activity to releasedopamine that is dependent of elevating intracellular calcium(Ca) concentrations. It has been proposed that a slow but consistent incrementof Ca could be responsible for aged DN death. Additionally, neuroinflammationis a well-established feature of PD, even though thedownstream events are still unclear.Methods: We had carried out a functional genomic analysis in a ratmodel that has neurodegeneration provoked by inflammation by the longtermexpression of TNFalpha in the SN delivered by an adenovector. Wefound that Plasma membrane Ca2+ Atpase 1 (PMCA1), a Ca pump, wasdownregulated and validated this finding by qPCR in two other rat PDmodels caused by inflammation. Every rat used for these tests presentedlocomotor alterations and DN degeneration. To study in vivo functionalityof the PMCA gene we used Drosophila melanogaster (DM) as a model.We downregulated PMCA in the DN using iRNA (th>PMCAiRNA) tostudy lifespan, Ca concentrations, DN degeneration, locomotor activityand dopamine concentration.Results: We found that PMCA1 gene was downregulated in theTNFalpha rat model. We confirmed the reduction of PMCA1 in other neurodegenerativemodels: chronic IL-1beta expression and 6OHDA/LPSadministration. To test the possible relevance of PMCA1 in DN in vivo,we analyzed th>PMCAiRNA flies and found that PMCA downregulationproduces a reduction of lifespan and Ca increments without neuronaldeath. Importantly, these changes in DN generate several locomotor alterations.Finally, the level of dopamine was higher in th>PMCAiRNA fliescompared to controls.Conclusions: We found PMCA1 is downregulated in three rat modelsof PD by inflammation. The reduction of PMCA in DM DN reproducedfeatures of other DM models of PD. Since DN are subjected to Cadependent-pacemaker, the decrease of PMCA1 could provoke a dysregulationin the Ca homeostasis, promoting their vulnerability. Theseresults postulate PMCA1 as a candidate to be a part of the DN degenerationprocess and suggest its possible involvement in DA differential vulnerabilityin PD.