Simulations of Diabetic and Non-Diabetic Peripheral Nerve Myelin Lipid Bilayers

Abstract

The multilayered myelin sheath is a critical component of both central and peripheral nervous systems, forming a protective barrier against axonal damage and facilitating the movement of nervous impulses. It is primarily composed of cholesterol (CHL1), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), sphingomyelin (SM), and galactosylceramide (GalCer) lipids. For rat sciatic nerve myelin (part of the peripheral nervous system, PNS), it has been found that cholesterol and unsaturated fatty acid contents are significantly lower in diabetic than in non-diabetic conditions. In this study, lipid compositions from experimental data are used to create four model rat sciatic nerve myelin lipid bilayers: PI-containing (nondiabetic and diabetic) and PS-containing (non-diabetic and diabetic), which were then simulated using the all-atom CHARMM36 force field. Simulation results of diabetic membranes indicate less rigid, more laterally expansive, and thinner bilayers as well as potentially reduced interactions between GalCer on opposing myelin leaflets, supporting a direct role of the cholesterol content decrease in instigating myelin deterioration and diabetic peripheral neuropathy. Compared to PI-lipids, PS-lipids were found to cause higher inter-lipid spacing and decreased order within membranes as a result of their smaller headgroup size and higher interlipid hydrogen bonding potential, which allow them to more frequently reside deeper in the membrane plane and produce pushing effects on other lipids. GalCer deuterium order parameters and non-diabetic headgroup-to-headgroup bilayer thicknesses were compared to experimental data, exhibiting close alignment, supporting the future usage of these models to study the PNS myelin sheath.

Metabolomics Analysis of DRG and Serum in the CCI Model of Mice

“…It is known that patients with diabetes suffer from peripheral neuropathic pain, which is caused by peripheral neuropathy caused by increased blood glucose [ 41 ]. Studies have shown that diabetes leads to peripheral neuropathy by reducing phospholipid synthesis to induce myelin abnormalities in nerves [ 42 , 43 ]. In this study, serum glucose and other carbohydrates of serum in the CCI group showed significant increases in the CCI group, suggesting that NP may lead to abnormal energy metabolism and elevated blood glucose in the serum; elevated blood glucose may further inhibit phospholipid synthesis and finally exacerbate the pain response.…”

All-Atom Modeling of Complex Cellular Membranes

“…Apart from plants, mammalian membrane models have been studied using the C36 lipid FF in our laboratory. Unlike plants whose major sphingolipids are glycosphingolipids, mammalian membranes contain more sphingomyelins (SMs) and ceramides (CERs). , The lipid composition can vary wildly depending on the species and organelles, which is evident from our models for ocular lens, stratum corneum (SC), , and peripheral nerve myelin . The modeling of the ocular lens focused on the influence of CHOL fraction and SM species where CHOL% ranged from 0 to 73 in the context of equal GPL/SM concentration.…”

“…142,143 The lipid composition can vary wildly depending on the species and organelles, which is evident from our models for ocular lens, 144 stratum corneum (SC), 145,146 and peripheral nerve myelin. 147 The modeling of the ocular lens focused on the influence of CHOL fraction and SM species where CHOL% ranged from 0 to 73 in the context of equal GPL/SM concentration. Two sets of models were developed for the SC, corresponding to the short periodicity phase (SPP) and the long periodicity phase (LPP).…”

“…The myelin sheath has a multilayered structure and is a critical component of both central and peripheral nerves. 158 Yuan et al 147 modeled the myelin sheath of rat sciatic nerves in a simplified one-layer and symmetric fashion. Four models were built and simulated with the C36 lipid FF to investigate the influences of PI vs PS and diabetes on membrane properties.…”