Activation of phosphatidylcholine signaling during oxidative stress in synaptic endings

MATEOS, MELINA*; URANGA, ROMINA* AMBOS AUTORES CONTRIBUYERON IGUALMENTE; SALVADOR, GABRIELA; GIUSTO, NORMA

NEUROCHEMISTRY INTERNATIONAL

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2008 vol. 53 p. 199 - 206

0197-0186

Oxidative stress and abnormally high levels of iron in the brain have beendemonstrated to be present in several neurodegenerative disorders such asParkinson’s disease (PD) and Alzheimer’s disease (AD) (Berg et al., 2001; Ong andFarooqui, 2005; Berg and Youdim, 2006; Quintana et al., 2006). Oxidative stress,resulting from increased brain iron levels, and possibly also from defects inantioxidant defence mechanisms, is widely believed to be associated with neuronaldeath in these pathologies (Aracena et al., 2006; Ke and Qian, 2007).Though a number of reports have described the intracellular events triggeredby oxidative stress very little is known about the role of lipid signal transductionduring oxidative injury (Petersen et al., 2007). Phospholipases specifically hydrolyzemembrane phospholipids and generate bioactive lipid second messengers whichparticipate in numerous cell signalling events (Eyster, 2007). Phosphatidylcholine(PC) is the most abundant class of glycerophospholipids in mammalian cellmembranes and it plays a key role in membrane structure, cell death, and cellularsignalling. In regard to signal transduction, PC is the main substrate forphospholipase D (PLD), yielding phosphatidic acid (PA) and choline upon cleavage (Exton 2000; Foster and Xu 2003). Involvement of the PLD pathway has beenproposed in several cellular events such as cytoskeletal rearrangement, vesicletrafficking, exocytosis, phagocytosis, oncogenesis, and neuronal and cardiacstimulation (Hattori and Kanfer, 1984; Liscovitch et al., 2000; Klein, 2005). PAgenerated by PLD can be further hydrolyzed by PA phosphatase type 2 (PAP2) inorder to generate another lipid second messenger, diacylglycerol (DAG). DAGderived from PC can be also generated by a specific phospholipase C (PC-PLC). Incontrast to DAG generated from phosphatidylinositol (4, 5) bisphosphate (PIP2) by4PIP2-PLC activity, the wave of DAG elicited from PC hydrolysis is generated moreslowly and occurs without elevation of intracellular Ca2+. PC-PLC activity has beenassociated with cellular events such as glutamate-induced nerve cell death, Fasinducedapoptosis, and cell mitogenic responses triggered by platelet-derivedgrowth factor(Li et al., 1998; Kim et al., 2001; Ramoni et al., 2004). Furthermore,PC-PLC appears to act downstream Ras but upstream Raf-1 during mitogenicsignal transduction (Cai et al., 1993). Though the physiological role of PC-PLC inimmune cells has been described extensively, very little is known about its functionin the central nervous system (Spadaro et al., 2006; Cecchetti et al., 2007).The coexistence of PLD and PC-PLC pathways has already been reported incerebral cortex synaptic endings and the existence of PC-PLC in the nervoussystem has been documented in immature cortical neurons and in a hippocampalnerve cell line, HT22 (Li et al., 1998; Mateos et al., 2006). However, the role of PCderivedlipid signalling in the central nervous system constitutes a newly emergingfield whose significance in pathological and physiological processes remains to beelucidated (Salvador et al., 2002; Klein, 2005; Salvador et al., 2005; Adibhatla et al.,2006). In this work we present evidence for the first time of the activation of PLD andPC-PLC pathways in synaptic endings subjected to oxidative injury triggered byFeSO4 overload.