Neuronal phospholipid deacylation is essential for axonal and synaptic integrity.
Recessively-inherited deficiency in the catalytic activity of calcium-independent phospholipase A2-beta (iPLA2β) and neuropathy target esterase (NTE) causes infantile neuroaxonal dystrophy and hereditary spastic paraplegia, respectively. Thus, these two related phospholipases have non-redundant functions that are essential for structural integrity of synapses and axons. Both enzymes are expressed in essentially all neurons and also have independent roles in glia. iPLA2β liberates sn-2 fatty acid and lysophospholipids from diacyl-phospholipids. Ca(2+)-calmodulin tonically-inhibits iPLA2β, but this can be alleviated by oleoyl-CoA. Together with fatty acyl-CoA-mediated conversion of lysophospholipid to diacyl-phospholipid this may regulate sn-2 fatty acyl composition of phospholipids. In the nervous system, iPLA2β is especially important for the turnover of polyunsaturated fatty acid-associated phospholipid at synapses. More information is required on the interplay between iPLA2β and iPLA2-gamma in deacylation of neuronal mitochondrial phospholipids. NTE reduces levels of phosphatidylcholine (PtdCho) by degrading it to glycerophosphocholine and two free fatty acids. The substrate for NTE may be nascent PtdCho complexed with a phospholipid-binding protein. Protein kinase A-mediated phosphorylation enhances PtdCho synthesis and may allow PtdCho accumulation by coordinate inhibition of NTE activity. NTE operates primarily at the endoplasmic reticulum in neuronal soma but is also present in axons. NTE-mediated PtdCho homeostasis facilitates membrane trafficking and this appears most critical for the integrity of axon terminals in the spinal cord and hippocampus. For maintenance of peripheral nerve axons, iPLA2β activity may be able to compensate for NTE-deficiency but not vice-versa. Whether agonists acting at neuronal receptors modulate the activity of either enzyme remains to be determined. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
Department of Cell Physiology & Pharmacology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK. pg8@le.ac.uk
Paul
P
Glynn
D000215:Acylation; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D002118:Calcium; D002147:Calmodulin / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D019150:Neuroaxonal Dystrophies / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D054512:Phospholipases A2, Calcium-Independent / Q000378:metabolism*; D015419:Spastic Paraplegia, Hereditary / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
D002147:Calmodulin; D005227:Fatty Acids; D007527:Isoenzymes; D008246:Lysophospholipids; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D054512:Phospholipases A2, Calcium-Independent; D002118:Calcium