Long chain polyunsaturated fatty acids are required for efficient neurotransmission in C. elegans

Abstract

The complex lipid constituents of the eukaryotic plasma membrane are precisely controlled in a cell-type-specific manner, suggesting an important, but as yet, unknown cellular function. Neuronal membranes are enriched in long-chain polyunsaturated fatty acids (LC-PUFAs) and alterations in LC-PUFA metabolism cause debilitating neuronal pathologies. However, the physiological role of LC-PUFAs in neurons is unknown. We have characterized the neuronal phenotype of C. elegans mutants depleted of LC-PUFAs. The C. elegans genome encodes a single Δ6-desaturase gene (fat-3), an essential enzyme for LC-PUFA biosynthesis. Animals lacking fat-3 function do not synthesize LC-PUFAs and show movement and egg-laying abnormalities associated with neuronal impairment. Expression of functional fat-3 in neurons, or application of exogenous LC-PUFAs to adult animals rescues these defects. Pharmacological, ultrastructural and electrophysiological analyses demonstrate that fat-3 mutant animals are depleted of synaptic vesicles and release abnormally low levels of neurotransmitter at cholinergic and serotonergic neuromuscular junctions. These data indicate that LC-PUFAs are essential for efficient neurotransmission in C. elegans and may account for the clinical conditions associated with mis-regulation of LC-PUFAs in humans.

Identification of two epoxide hydrolases in Caenorhabditis elegans that metabolize mammalian lipid signaling molecules

“…C18 and C20 polyunsaturated fatty acids (PUFAs) have been shown to effect directed sperm movement towards the spermatheca and the formation of synaptic vesicles in neuronal tissues. [18,19] FAT-3 mutants lack the delta6 fatty acid desaturase and so cannot convert linoleic acid into C20 PUFAs because this desaturase activity is a prerequisite to subsequent elongase activity. [20] These mutants show a number of defects which are rescued by dietary supplementation of C20 and C18 PUFAs, including smaller brood size, alterations in the defecation cycle, and defects in chemotaxis.…”

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

“…This effect occurred already after short-term exposure of the worms to 10 µM 17,18-EEQ, whereas long-term feeding and much higher concentrations were required to achieve similar effects with AA or EPA. Also other authors found that high concentrations and a minimal time of about 24 h are required to restore the phenotype of fat-3 mutants by C20-PUFA supplementation [43][44][45][46][47][48]. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with the mutant but to a lesser extent also with wild-type worms.…”

“…Within this process, 17,18-EEQ might also stimulate the release of neuropeptides that act as neurohormones onto body muscles. Providing a first link between C20-PUFA deficiency and neurotransmission, fat-3(lg8101) worms were shown to release abnormally low levels of neurotransmitters at cholinergic and serotonergic neuromuscular junctions and to be depleted of synaptic vesicles [43].…”

“…Within this process, 17,18-EEQ might also stimulate the release of neuropeptides that act as neurohormones onto body muscles. Providing a first link between C20-PUFA deficiency and neurotransmission, fat-3(lg8101) worms were shown to release abnormally low levels of neurotransmitters at cholinergic and serotonergic neuromuscular junctions and to be depleted of synaptic vesicles [43].The O2-ON response of C. elegans and ischemia/reperfusion injury of mammalian organs are quite different in terms of their final outcomes. However, as elaborated in the present study, they may share common mechanisms of CYP-eicosanoid formation and action.…”

Docosahexaenoic Acid (DHA), in the Prevention and Treatment of Neurodegenerative Diseases

“…Other evidences suggest that some membrane proteins may facilitate the transport of ALN and/or DHA through the hematoencephalic barrier. One of these transporters has been identified as a caveolin binding protein type or CD36 (Williard et al, 2001 ;Lesa et al, 2003). However, plasma levels of LCPUFA are poorly correlated with the dietary intake of the precursors (Kalant & Cianflone, 2004).…”