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

GABRIELA A. SALVADOR

Mar del Plata

Congreso; Congreso Anual de la Sociedad Argentina de Investigacion Clinica; 2019

SAIC

Salvador GA, Simposio Nutrition, metabolism, genetic, social and cultural habits as determinants for illness vulnerability. Lipids at the crossroad of α-synuclein function and dysfunction: new insights into neurodegeneration. Reunión Anual de la Sociedad Argentina de Investigación Clínica SAIC- Libro de resúmenes: Revista Medicina. 12 al 16 de noviembre de 2019, Mar del Plata, Argentina.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 named, Lewy bodies, is a hallmark of a class of neurodegenerative disorders grouped as sinucleinopathies, being Parkinson´s disease the most prevalent. The different ways in which α-synuclein interacts with lipids, is one intriguing characteristic and also an open question related with both its biological function and pathogenesis. In our lab, we are mainly focused in 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; in particular, are associated with synaptic injury induced by oxidative stress and inflammatory response. Based on these previous findings and the intersections between α-synuclein and lipids biology, we recently investigated the role of PLD signaling in a sinucleinopathy cellular model. The overexpression of Wild Type (WT) α-synuclein was found to trigger the 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 exhibited 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 bodies 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. WT α-synuclein overexpression also triggered the nuclear localization of the lipogenic transcription factor SREBP-2. Enhancers of α-syn aggregation ( manganese and bortezomib) increased LD content. WT α-syn overexpression also induced Acyl-CoA synthetase activation which explained, at least in part, the increase in TAG, a rather unusual occurrence in healthy neurons. Pharmacological inhibition of TAG synthesis turned the neurons more vulnerable to the presence of WT α-synuvlein.