1. “Regulation of phosphatidylcholine-derived signaling during oxidative stress. Participation of synaptic membrane rafts

MATEOS MELINA; SALVADOR, GABRIELA ALEJANDRA; GIUSTO NORMA

Florencia

Congreso; 8th IBRO World Congress of Neuroscience.; 2011

Ibro

Regulation of phosphatidylcholine-derived signaling during oxidative stress. Participation of synaptic membrane rafts. Mateos MV; Salvador GA and Giusto NM.   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). Such disorders are related to abnormal synaptic signalling, mainly due to the first neurodegenerative signs  appear in synapses. Moreover, synaptic endings are considered sites where signal transduction pathways are heavily concentrated and where signalling events exert far-reaching effects on neuronal plasticity and survival. We have previously demonstrated that iron-induced oxidative stress stimulates diacylglycerol (DAG) generation from phosphatidylcholine (PC) in isolated cerebral cortex synaptic endings (Syn) obtained from adult (4-month old) and aged rats (28-month old). The rise in this second lipid messenger derived from PC was due to the activation of a PC-specific phospholipase C (PC-PLC) and a phospholipase D (PLD) (Mateos et al., 2008). In this work we further studied the mechanisms that govern synaptic DAG signaling during oxidative injury.  DAG formation was differentially affected by the use of PIP2-PLC, PKC and ERK kinases inhibitors (U73122, BIM and U0126, respectively). U73122 partially inhibited DAG generation in Syn exposed to oxidative stress, from both adult and aged rats. However, only in Syn from aged animals, PKC and ERK inhibition showed to decrease DAG generation induced by oxidative injury. It was also demonstrated that PC-PLC and PLD1 were localized in membrane rafts (MR) isolated from the synaptic endings, whereas PLD2 isoform was excluded from theses microdomains (Mateos et al., 2010). In this regard, we observed that the co-localization of PLD1 and PC-PLC with flotillin-1 (a MR marker), and the DAG generation were not affected neither by aging nor by oxidative stress in isolated membrane rafts. In the presence of iron, lipid peroxidation levels (measured as malondialdehyde formation) were increased in synaptic membranes from adult and aged rats. However, this iron-induced increase in lipid peroxides observed in Syn was absent in MR. This phenomenon was in accordance with a decreased polyunsaturated fatty acid composition in MR with respect to Syn. Summarizing, our results show that in the rat synaptic endings exposed to oxidative injury: a) PC hydrolysis and DAG formation are differentially regulated by aging and b) PC-PLC and PLD1 localization in MR could be a mechanism for preventing DAG rise.   IBRO alumni: "III IBRO-FOGARTY NEUROSCIENCE SCHOOL- Neurons and Glial Cells: life, death and resurrection" September 18-30, 2006. Pinamar, Buenos Aires, Argentina.