Suppression of MAPK attenuates neuronal cell death induced by activated glia-conditioned medium in alpha-synuclein overexpressing SH-SY5Y cells

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disease with characteristics and symptoms that are well defined. Nevertheless, its aetiology remains unknown. PD is characterized by the presence of Lewy bodies inside neurons. aα-Synuclein (aα-syn) is a soluble protein present in the pre-synaptic terminal of neurons. Evidence suggests that aα-syn has a fundamental role in PD pathogenesis, given that it is an important component of Lewy bodies localized in the dopaminergic neurons of PD patients. Methods: In the present study, we investigated the influence of wild type (WT) and A30P aα-syn overexpression on neuroblastoma SH-SY5Y toxicity induced by the conditioned medium (CM) from primary cultures of glia challenged with lipopolysaccharide (LPS) from Escherichia coli. Results: We observed that SH-SY5Y cells transduced with aα-syn (WT or A30P) and treated with CM from LPS-activated glia cells show evidence of cell death, which is not reverted by NF-ΚB inhibition by sodium salicylate or by blockage of P50 (NF-ΚB subunit). Furthermore, the expression of A30P aα-syn in neuroblastoma SH-SY5Y decreases the cell death triggered by the CM of activated glia versus WT aα-syn or control group. This effect of A30P aα-syn may be due to the low MAPK42/44 phosphorylation. This finding is substantiated by MEK1 inhibition by PD98059, decreasing LDH release by CM in SH-SY5Y cells. Conclusion: Our results suggest that SH-SY5Y cells transduced with aα-syn (WT or A30P) and treated with CM from LPS-activated glia cells show cell death, which is not reverted by NF-ΚB blockage. Additionally, the expression of A30P aα-syn on neuroblastoma SH-SY5Y leads to decreased cell death triggered by the CM of activated glia, when compared to WT aα-syn or control group. The mechanism underlying this process remains to be completely elucidated, but the present data suggest that MAPK42/44 phosphorylation plays an important role in this process. Trial Registration: PROSPERO: CRD42015020829