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

ERDHARDT, B; FRENKEL, LIA; SILVA, BERENICE; ALLO, M; CASTAÑO, E; MARCORA, SILVINA; BOCHICCHIO, PA; FARIAS M.I; HOTCH, C; LEAL, MC; CASABONA, JC; BODIN, D; FERRARI , CC; ARIEL CHERNOMORETZ; F PITOSSI

Nice

Congreso; International Parkinson and Movement Disorder Society; 2019

Parkinson?s disease and Movement Disorders.

Objective: To identify genes involved in the degeneration of the dopaminergic neurons (DN) of the substantia nigra (SN) by inflammation.Background: Parkinson?s disease (PD) is characterized by a progressive death of DN within the SN. The molecular bases of the DN degeneration are unknown. DN show a peculiar pacemaker activity to release dopamine that is dependent of elevating intracellular calcium (Ca) concentrations. It has been proposed that a slow but consistent increment of Ca could be responsible for aged DN death. Additionally, neuroinflammation is a well-established feature of PD, even though the downstream events are still unclear. Methods: We had carried out a functional genomic analysis in a rat model that has neurodegeneration provoked by inflammation by the long-term expression of TNFalpha in the SN delivered by an adenovector. We found that Plasma membrane Ca2+ Atpase 1 (PMCA1), a Ca pump, was downregulated and validated this finding by qPCR in two other rat PD models caused by inflammation. Every rat used for these tests presented locomotor alterations and DN degeneration. To study in vivo functionality of the PMCA gene we used Drosophila melanogaster (DM) as a model. We downregulated PMCA in the DN using iRNA (th>PMCAiRNA) to study lifespan, Ca concentrations, DN degeneration, locomotor activity and dopamine concentration. Results: We found that PMCA1 gene was downregulated in the TNFalpha rat model. We confirmed the reduction of PMCA1 in other neurodegenerative models: chronic IL-1beta expression and 6OHDA/LPS administration. To test the possible relevance of PMCA1 in DN in vivo, we analyzed th>PMCAiRNA flies and found that PMCA downregulation produces a reduction of lifespan and Ca increments without neuronal death. Importantly, these changes in DN generate several locomotor alterations. Finally, the level of dopamine was higher in th>PMCAiRNA flies compared to controls. Conclusions: We found PMCA1 is downregulated in three rat models of PD by inflammation. The reduction of PMCA in DM DN reproduced features of other DM models of PD. Since DN are subjected to Ca dependent-pacemaker, the decrease of PMCA1 could provoke a dysregulation in the Ca homeostasis, promoting their vulnerability. These results postulate PMCA1 as a candidate to be a part of the DN degeneration process and suggest its possible involvement in DA differential vulnerability in PD.