Phospholipase D1 downregulation by α-synuclein: Implications for neurodegeneration in Parkinson's disease

CONDE, MELISA A.; ALZA, NATALIA P.; IGLESIAS GONZÁLEZ, PABLO A.; SCODELARO BILBAO, PAOLA G.; SÁNCHEZ CAMPOS, SOFÍA; URANGA, ROMINA M.; SALVADOR, GABRIELA A. AUTOR CORRESP

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

ELSEVIER SCIENCE BV

Año: 2018 vol. 1863 p. 639 - 650

1388-1981

We have previously shown that phospholipase D (PLD) pathways have a role in neuronal degeneration; inparticular, we found that PLD activation is associated with synaptic injury induced by oxidative stress. In thepresent study, we investigated the effect of α-synuclein (α-syn) overexpression on PLD signaling. Wild Type(WT) α-syn was found to trigger the inhibition of PLD1 expression as well as a decrease in ERK1/2 phosphorylationand expression levels. Moreover, ERK1/2 subcellular localization was shown to be modulated by WT α-syn in a PLD1-dependent manner. Indeed, PLD1 inhibition was found to alter the neurofilament network and Factindistribution regardless of the presence of WT α-syn. In line with this, neuroblastoma cells expressing WT α-syn exhibited a degenerative-like phenotype characterized by a marked reduction in neurofilament light subunit(NFL) expression and the rearrangement of the F-actin organization, compared with either the untransfected orthe empty vector-transfected cells. The gain of function of PLD1 through the overexpression of its active formhad the effect of restoring NFL expression in WT α-syn neurons. Taken together, our findings reveal an unforeseenrole for α-syn in PLD regulation: PLD1 downregulation may constitute an early mechanism in the initialstages of WT α-syn-triggered neurodegeneration