Phosphatidic acid signaling participates in the neurodegeneration induced by alpha-synuclein

CONDE, M.A.; IGLESIAS GONZALEZ P.A.; ALZA N.P.; URANGA, R.M.

Córdoba

Congreso; LII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2016

Pathological accumulation of α-synuclein (α-syn) is a hallmark of Parkinson?s disease. Even though the physiological function of this protein is still unknown, it is well accepted that its aggregation triggers degeneration and death in dopaminergic neurons. One intriguing characteristic of α-syn is its lipid binding affinity. We have previously reported that overexpression of α-syn triggers an increase in neutral lipid and fatty acid content (SAIB 2014-2015) in dopaminergic neurons. In this work, we investigated the state of phosphatidic acid (PA) signaling in human neurons overexpressing α-syn. Specifically, we studied the state of phospholipase D (PLD) pathway that catalyzes PA generation by phosphatidylcholine hydrolysis. We detected a diminished expression of PLD1 in α-syn neurons. Overexpression of α-syn inhibited ERK nuclear localization and the expression of the neuronal marker neurofilament (NF). PLD1 pharmacological inhibition (EVJ) demonstrated that both ERK nuclear localization and NF expression were dependent on this pathway. Enhancers of α-syn toxicity such as Cu and 6-OHDA further diminished PLD1 expression. Our results demonstrate that α-syn accumulation triggers neurodegeneration through the inhibition of PLD1 pathway, thus affecting ERK signaling and NF expression.