Involvement of Cytosolic Phospholipase A2, Calcium Independent Phospholipase A2 and Plasmalogen Selective Phospholipase A2 in Neurodegenerative and Neuropsychiatric Conditions

Enzymes belonging to the PLA2 superfamily catalyze the hydrolysis of unsaturated fatty acids from the sn-2 position of glycerol moiety of neural membrane phospholipids. The PLA2 superfamily is classified into cytosolic PLA2 (cPLA2), calcium-independent PLA2 (iPLA2), plasmalogen-selective PLA2 (PlsEtn-PLA2) and secretory PLA2 (sPLA2). PLA2 paralogs/splice variants/isozymes are part of a complex signal transduction network that maintains cross-talk among excitatory amino acid and dopamine receptors through the generation of second messengers. Individual paralogs, splice variants and multiple forms of PLA2 may have unique enzymatic properties, tissue and subcellular localizations and roles in various physiological and pathological situations, hence tight regulation of all PLA2 isoforms is essential for normal brain function. Quantitative RT-PCR analyses show significantly higher expression of iPLA2 than cPLA2 in all regions of the rat brain. Upregulation of the cPLA2 family is involved in degradation of neural membrane phospholipids and generation of arachidonic acid-derived lipid metabolites that have been implicated in nociception, neuroinflammation, oxidative stress and neurodegeneration. In contrast, studies using a selective iPLA2 inhibitor, bromoenol lactone, or antisense oligonucleotide indicate that iPLA2 is an important “housekeeping” enzyme under normal conditions, whose activity is required for the prevention of vacuous chewing movements, and deficits in prepulse inhibition of the auditory startle reflex, a finding in human patients with schizophrenia. These studies support the view that PLA2 activity may not only play a crucial role in neurodegeneration, but depending on the isoform, could also be essential in prevention of neuropsychiatric diseases. These findings could open new doors for understanding and treatment of neurodegenerative and neuropsychiatric diseases.