Putting It All Together – CFS is a Disease of Increased Phospholipase (PLA) Activity - Chaudhuri and Behan suggest increased choline levels contribute to cognitive dysfunction (effortful task processing) and reduced ATP levels impair aerobic metabolism and contribute to the exercise intolerance seen in CFS. What might increased brain choline and decreased ATP production have in common? Chaudhuri and Behan believe both are due to increased phospholipase (PLA) activity. This appears to suggest they believe increased PLA activity occurs not just in the brain but is system wide. Since PLA is ubiquitous in the body increased PLA activity could affect a wide variety of tissues.
Phospholipases (PLA’s) – are a superfamily of esterases that release phospholipids ‘moieties’ (fractions) including choline when they hydrolyze (break) the ester bonds in lipid membranes. Aside from actual trauma or lipid peroxidation (free radical damage) phospholipid release from cell membranes is usually caused by phospholipase activity. Phospholipids in the CNS cell membranes are high in polyunsaturated fatty acids (PUFA’s) and PUFA metabolism is ‘stringently controlled’ by PLA2 (and acetyltransferase). Normally when fatty acids are released by PLA2 they are rapidly taken up by membrane phospholipids by an energy dependent mechanism using CoA and ATP.
Phospholipase activity releases factors that exert widely varying effects in the cell. Phospholipids play a key role in regulating the release of arachidonic acid, the precursor of eicocanisoid synthesis. The eicocansoids (prostaglandins, thromboxanes, leukotrienes) mediate (trigger) the inflammatory process. A marker of cellular injury, the inflammatory process begins with the release of AA. AA is broken up to produce pro-inflammatory mediators such as prostaglandins (COX 1, 2) and leukotrienes. Prostaglandins then combine with cellular receptors to initiate signaling cascades which utilize G-proteins and cyclic CMP (cAMP) to produce pro-inflammatory substances.
PLA2 activity has been implicated in the pathology of a number of neurodegenerative diseases including Alzheimer’s and is thought to play a role in neuronal plasticity (Sun et. al. 2004). The activation of the P2Y nucleotide receptor on astrocytes triggers ‘reactive gliosis’, a process implicated in these neurodegenerative diseases and which Chaudhuri and Behan believe may be occurring in CFS.
TRIGGERING PHOSPHOLIPASE ACTIVITY - Why phospholipase activity would be increased in CFS patients is unclear. CFS patients appear to be subject, however, to several factors (infection, increased neurotransmitter/ cytokine levels, oxidative stress, neurotoxins) that could trigger phospholipase activity. Chaudhuri et. al. note that infection and/or neurotoxins can produce prolonged changes in membrane functioning (Chaudhuri et. al. 2003). The authors suggest the adaptation of the host cell to either a pathogen or its exotoxin (neurotoxin) could result in a long term derangement of the membranes
