The unsaturated brain: An evolutionary compromise?

Abstract

Tothe Editor:The brain has ahigh content of polyunsaturated fattyacids (PUFAs), which are critical for neurodevelopment, neuro-transmission, rapid metabolic turnover and repair [Davletov andMontecucco, 2010]. The high susceptibility of PUFAs to peroxida-tion mediated by reactive oxygen species (ROS), however, results inan increased vulnerability of the brain to oxidative damage [Barja,2004]. The production of ROS by mitochondria (e.g. electrontransport chain; alpha-ketoglutarate dehydrogenase in the Krebscycle), peroxisomes or microglia is further exacerbated by the highoxygen consumption of brain [Barja, 2004; Adam-Vizi, 2005].Moreover,theoxidativechallengeforbrainisworsenbytherelativepaucity of antioxidant enzymes compared with other organs.Considering the prominent role of neuronal signalling pathways asregulators of organismal response to environmental stimuli, PUFAsmay increase the oxidative stress threat for this system, hencejeopardizing its normal function.The continuous degradation and synthesis of RNAs is responsibleof the metabolic changes essential for cell survival, but also of therapid organismal adaptation to new environmental conditions.Oxidative damage to both coding- and non-coding RNAs and theirdegradation control system may therefore affect the regulation ofgene expression and, potentially, result in protein synthesis failure.In turn, this failure may impair the organismal capacity of flexiblyadapting to a novel or unusual input from the internal or externalenvironment [Nunomura et al., 2009; He, 2010]. An importantconsequence of this impairment is the development of neurode-generative disorders. Accumulating evidence suggests that oxida-tiveRNAdamagemayactivelybeinvolvedinthepathomechanismsof neurodegeneration [Nunomura et al., 2009]. Because of itsbiochemical structure, RNAs may be more susceptible to oxidativeinsults than DNA [Nunomura et al., 1999]. RNAs may also be animportant target of oxidation because they are relatively abundantin the cell and they are mostly located in the vicinity ofmitochondria, which are the primary source of ROS [Nunomuraet al., 1999]. As a consequence, oxidative damage to RNA ratherthan DNA may be a more proximate cause of impairment inneuronal functioning through the alteration of brain geneexpression machinery. Specific protective mechanisms of RNAsand their degradation control would be therefore expected to occurin neurons [Houseley and Tollervey, 2009]. May the highsusceptibility of PUFAs to peroxidation indirectly play a role inthe defence system of RNAs and, therefore, of the gene expressionregulatory system inthenervous system? Although thefunctions ofPUFAs in the nervous system are still far from being fullyunderstood, recent studies have shown that PUFAs may affect theexpression of many genes and that these effects appear to beindependent of any changes in membrane composition [de Urquizaet al., 2000; Kitajka et al., 2002, 2004]. It is plausible to speculatethatthehighvulnerabilitytoperoxidationoffreePUFAsinneurons,coupled with their relative abundance in the brain, might play apassive protective role of RNAs, hence limiting their oxidation.Somesupportforthishypothesiscomesfromarecentstudythathassuggested a potential antioxidant role of PUFAs [Kim et al., 2010].Notably, supplementation with omega-3 or omega-6 PUFAs ofcultured neurons from mice lacking the gene encoding palmitoyl-protein thioesterase-1, which mimic infantile neuronal ceroidlipofuscinosis, reduced ROS levels that are normally very high inthese cells [Kim et al., 2010]. Under this scenario, a second questionarises. As PUFAs are major components of neural membranephospholipids and have a critical role in brain signal transductionand neuroplasticity [Davletov and Montecucco, 2010], can PUFAsembedded in the cell membrane contribute to the protection ofRNAs? Weinfer thatthey canlimitthediffusion ofROSinto thecellbecauseoftheirpronenesstobeperoxidized.Thismechanismwouldlimit the intercellular transmission of ROS and that the oxidativecascade will spread to RNAs. Peroxidation of PUFAs in themembrane phospholipids has, however, a number of negativedownstream effects on the cell, such as the decrease in fluidity andincrease in permeability. Consequently, it is of fundamentalimportancetheexistenceofaturnovermechanismthatcompensatesforoxidativePUFAdamage.Manystudieshaveprovidedawealthofevidence that there may be at least two mechanisms regulating the