Sphingolipid alterations in the cross-talk between primed microglia-and dopaminergic neurons

Chronic inflammation plays a key role in neurodegenerative disease and in particular in Parkinson’s disease, where microglial activation emerged as crucial. Despite intensive studies, the relevant changes associated to microglia activation and its negative effects on dopaminergic neurons remain elusive. We investigated the role of sphingolipids as possible mediators in both microglial priming and microglial-induced neuronal damage. We first observed that priming of microglia leads to increased cellular and extracellular sphingosine-1 phosphate (S1P), which acts as a proinflammatory mediator. GlcCer accumulation also occurred, promoting microglial proliferation. In addition, exposure of dopaminergic neurons to primed microglia medium lead to a marked increase of ceramide and S1P reduction, which emerged as critical in inducing caspase-3 activation and neuron apoptosis. Overall, this study reveals multiple sphingolipid metabolic switches in both microglia and dopaminergic neurons. Understanding how these metabolic switches occur and affect essential microglia and neuronal pathways will possibly help devise strategies aimed to protect dopaminergic neurons in degeneration.