Haughey, N. J. | Search bioRxiv

bioRxiv2019

Inhibition of neutral sphingomyelinase-2 facilitates remyelination

For reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNF and IL-1{beta} is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNF and IL-1{beta} with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2 in vivo increased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

molecular biology↗

bioRxiv2019

Monocarboxylate transporter 1 in Schwann cells is critical for maintenance of sensory nerve myelination during aging

Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/-, MCT1f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, enlarged node length and reduced mechanical sensitivity were evident in aged P0-Cre+/-, MCT1f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein (MAG), and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the essential role of SC MCT1 in both SC metabolism and peripheral nerve maturation and aging.\n\nMain PointsO_LISC MCT1 deficiency causes hypomyelination of sensory, but not motor, axons during aging\nC_LIO_LIEnlarged node length of sensory axons is evident in mutant mouse with SC-specific MCT1 deletion\nC_LIO_LISelective ablation of MCT1 within SCs impairs glycolytic and mitochondrial functions\nC_LIO_LISC-specific MCT1 deficiency impairs proteins that regulate myelin and lipid metabolism in peripheral nerves\nC_LI

neuroscience↗