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 been demonstrated to be present in several neurodegenerative disorders such as Parkinson´s disease (PD) and Alzheimer´s disease (AD) (Berg et al., 2001; Ong and Farooqui, 2005; Berg and Youdim, 2006; Quintana et al., 2006). Oxidative stress, resulting from increased brain iron levels, and possibly also from defects in antioxidant defence mechanisms, is widely believed to be associated with neuronal death in these pathologies (Aracena et al., 2006; Ke and Qian, 2007). Though a number of reports have described the intracellular events triggered by oxidative stress very little is known about the role of lipid signal transduction during oxidative injury (Petersen et al., 2007). Phospholipases specifically hydrolyze membrane phospholipids and generate bioactive lipid second messengers which participate in numerous cell signalling events (Eyster, 2007). Phosphatidylcholine (PC) is the most abundant class of glycerophospholipids in mammalian cell membranes and it plays a key role in membrane structure, cell death, and cellular signalling. In regard to signal transduction, PC is the main substrate for phospholipase D (PLD), yielding phosphatidic acid (PA) and choline upon cleavage (Exton 2000; Foster and Xu 2003). Involvement of the PLD pathway has been proposed in several cellular events such as cytoskeletal rearrangement, vesicle trafficking, exocytosis, phagocytosis, oncogenesis, and neuronal and cardiac stimulation (Hattori and Kanfer, 1984; Liscovitch et al., 2000; Klein, 2005). PA generated by PLD can be further hydrolyzed by PA phosphatase type 2 (PAP2) in order to generate another lipid second messenger, diacylglycerol (DAG). DAG derived from PC can be also generated by a specific phospholipase C (PC-PLC). In contrast to DAG generated from phosphatidylinositol (4, 5) bisphosphate (PIP2) by PIP2-PLC activity, the wave of DAG elicited from PC hydrolysis is generated more slowly and occurs without elevation of intracellular Ca2+. PC-PLC activity has been associated with cellular events such as glutamate-induced nerve cell death, Fas-induced apoptosis, and cell mitogenic responses triggered by platelet-derived growth 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 mitogenic signal transduction (Cai et al., 1993). Though the physiological role of PC-PLC in immune cells has been described extensively, very little is known about its function in the central nervous system (Spadaro et al., 2006; Cecchetti et al., 2007). The coexistence of PLD and PC-PLC pathways has already been reported in cerebral cortex synaptic endings and the existence of PC-PLC in the nervous system has been documented in immature cortical neurons and in a hippocampal nerve cell line, HT22 (Li et al., 1998; Mateos et al., 2006). However, the role of PC-derived lipid signalling in the central nervous system constitutes a newly emerging field whose significance in pathological and physiological processes remains to be elucidated (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 and PC-PLC pathways in synaptic endings subjected to oxidative injury triggered by FeSO4 overload