Lipids at the crossroad of α-synuclein function and dysfunction: new insights into neurodegeneration

Abstract

Since its discovery, the study of the biological role of α- synuclein has been the subject of increasing interest. Its aggregation and accumulation in intracellular structures called Lewy bodies are a hallmark of a class of neurodegenerative disorders grouped as synucleinopathies, of which Parkinson ́s disease is the most prevalent. The different ways in which α- synuclein interacts with lipids are not only an intriguing characteristic but also an open question related with its biological function and pathogenesis. In our lab, we are mainly focused on the study of lipid signaling and metabolism in different models of neuronal injury. Phosphatidic acid, a bioactive lipid produced by the activation of Phospholipase D (PLD), governs multiple signaling pathways. We have previously demonstrated that PLD pathways are involved in neuronal degeneration and are, in particular, associated with synaptic injury induced by oxidative stress and inflammatory response. Based on these findings and taking into account the intersections between α-synuclein and lipid biology, we have recently investigated the role of PLD signaling in a synucleinopathy cellular model. The overexpression of wild type (WT) α-synuclein was found to trigger an inhibition of phosphatidic acid production through PLD1 downregulation as well as a decrease in ERK1/2 phosphorylation. Moreover, ERK1/2 subcellular localization and nuclear sequestration were shown to be modulated by the overexpression of α-synuclein in a PLD1-dependent manner. In addition to the changes observed in PLD signaling, neuroblastoma cells expressing WT α-synuclein were found to exhibit a degenerative-like phenotype characterized by a marked reduction in the neurofilament light subunit (NFL). This NFL loss has also been reported in studies performed in post-mortem brains from Lewy body dementia. The gain of function of PLD1 through the overexpression of its active form had the effect of restoring NFL expression in WT α-synuclein neurons. Lipid metabolism was also altered in neurons overexpressing several forms of α-synuclein (WT or the mutant A53T). The most conspicuous evidence supporting a metabolic switch induced by the different forms of α-synuclein was the presence of lipid droplets. The accumulation of lipid droplets is a rare and unusual entity for the neuronal phenotype. In this respect, WT α-synuclein overexpression was observed to trigger the nuclear localization of the lipogenic transcription factor SREBP-2 and enhancers of protein aggregation (manganese and bortezomib) were found to increase lipid droplets content. WT α-synuclein overexpression also induced Acyl-CoA synthetase activation, which explained, at least in part, the increase in triacylglycerol (usually stored in lipid droplets). The pharmacological inhibition of triacylglycerol synthesis turned neurons more vulnerable to the presence of WT α-synuclein. Taken together, our findings reveal unforeseen roles for α- synuclein in lipid biology, namely i) PLD1 downregulation associated with NF loss and ii) a metabolic switch with increased triacylglycerol content. Both the decrease in phosphatidic acid levels by PLD1 inhibition and the increase in lipid droplets could be considered as early markers of the neurodegenerative process triggered in synucleopathies