De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination

Abstract

Montani et al. reveal that de novo fatty acid synthesis by Schwann cells, mediated by fatty acid synthase, contributes fundamentally to driving myelination in the peripheral nervous system. They identify lipogenic activation of the PPARγ transcriptional network as a putatively involved functional mechanism.

De novo mutation inELOVL1causes ichthyosis,acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy

“…FAs also modulate PPARγ activity, especially in the PNS. In mice, decreased C16-FA availability downregulated the PPARγ transcriptional network in Schwann cells 23. Restoring PPARγ activity in those mice rescued PNS myelination.…”

“…One hypothetical explanation may be the Schwann cells' localisation outside the blood-brain barrier, in contrast to oligodendrocytes,27 which would guarantee access to the bloodstream for FA uptake. Alternative FA sources for Schwann cells may derive from lipolysis of epineurial adipocytes23 or from compensatory synthesis via an alternative pathway. The latter phenomenon was observed in patients with fatty acid 2-hydroxylase deficiency (OMIM#612319), whose PNS was also spared.…”

Monocarboxylate transporter 1 in Schwann cells contributes to maintenance of sensory nerve myelination during aging

“…Myelin membranes have a very high lipid‐to‐protein ratio, in which lipids constitute 70–80% of myelin (O'Brien, Sampson, & Stern, ). Lipid biosynthesis is thus critical for SCs during both developmental myelination and maintenance of myelin sheaths during maturation and aging; and abnormalities of lipid metabolism can directly cause hypomyelination (Montani et al, ; Schmitt, Castelvetri, & Simons, ). Though the two most abundant myelin proteins, P0 and MBP, were present in normal amounts, several lipids, including sphingomyelin, triacylyglycerides, and diacylglycerides were reduced in sensory peripheral nerves lacking SC MCT1.…”

“…Our hypothesis is that impaired glycolytic and oxidative metabolism in SCs leads to increased utilization and impaired synthesis of SC lipids, thus removing a critical substrate for the maintenance of myelin lipids. Though not previously investigated following abnormalities in MCT1, mitochondrial defects caused reduced pyruvate oxidation, aberrant SC lipid metabolism, and peripheral nerve injury (Riviere et al, ); and fatty acid synthesis in SCs is necessary for myelination (Montani et al, ). Thus, the observed reduction in mitochondrial oxidative phosphorylation in MCT1‐deficient SCs is likely one mechanism for aberrant lipid metabolism.…”

“…Though not previously investigated following abnormalities in MCT1, mitochondrial defects caused reduced pyruvate oxidation, aberrant SC lipid metabolism, and peripheral nerve injury (Riviere et al, 2009); and fatty acid synthesis in SCs is necessary for myelination (Montani et al, 2018). Thus, the observed reduction in mitochondrial oxidative phosphorylation in MCT1-deficient SCs is likely one mechanism for aberrant lipid metabolism.…”