An electroceutical approach enhances myelination via upregulation of lipid biosynthesis in the dorsal root ganglion

As the myelin sheath is crucial for neuronal saltatory conduction, loss of myelin in the peripheral nervous system (PNS) leads to demyelinating neuropathies causing muscular atrophy, numbness, foot deformities and paralysis. Unfortunately, few interventions are available for such neuropathies, because previous pharmaceuticals have shown severe side effects and failed in clinical trials. Therefore, exploring new strategies to enhance PNS myelination is critical to provide solution for such intractable diseases. This study aimed to investigate the effectiveness of electrical stimulation (ES) to enhance myelination in the mouse dorsal root ganglion (DRG) – an ex vivo model of the PNS. Mouse embryonic DRGs were extracted at E13 and seeded onto Matrigel-coated surfaces. After sufficient growth and differentiation, screening was carried out by applying ES in the 1-100 Hz range at the beginning of the myelination process. DRG myelination was evaluated via immunostaining at the intermediate (19 DIV) and mature (30 DIV) stages. Further biochemical analyses were carried out by utilizing RNA sequencing, qPCR and biochemical assays at both intermediate and mature myelination stages. Imaging of DRG myelin lipids was carried out via time-of-flight secondary ion mass spectrometry (ToF-SIMS). With screening ES conditions, optimal condition was identified at 20 Hz, which enhanced the percentage of myelinated neurons and average myelin length not only at intermediate (129% and 61%) but also at mature (72% and 17%) myelination stages. Further biochemical analyses elucidated that ES promoted lipid biosynthesis in the DRG. ToF-SIMS imaging showed higher abundance of the structural lipids, cholesterol and sphingomyelin, in the myelin membrane. Therefore, promotion of lipid biosynthesis and higher abundance of myelin lipids led to ES-mediated myelination enhancement. Given that myelin lipid deficiency is culpable for most demyelinating PNS neuropathies, the results might pave a new way to treat such diseases via electroceuticals.

Enhanced axonal Neuregulin-1 type-III signaling ameliorates disease severity in a CMT1B mouse model

ABSTRACTCharcot–Marie–Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) with heterogeneous pathogenesis and no available treatment. Axonal Neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here, we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain of function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor TACE/ADAM17, also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.

Molecular and immunogenic features of myelin lipids: incitants or modulators of multiple sclerosis?

Myelin lipids have long been thought to play intriguing roles in the pathogenesis of multiple sclerosis (MS). This review summarizes current understanding of the molecular basis of MS with emphasis on the: (i.) physico-chemical properties, organization and accessibility of the lipids and their distribution within the myelin multilayer; (ii.) characterization of myelin lipid structures, and structure–function relationships relevant to MS mechanisms, and; (iii.) immunogenic and other features of lipids in MS including molecular mimicry, lipid enzyme genetic knockouts, glycolipid-reactive NKT cells, and monoclonal antibody-induced remyelination. New findings associate anti-lipid antibodies with pathophysiological biomarkers and suggest clinical utility. The structure of CD1d-lipid complexed with the lipophilic invariant T cell receptor (iTCR) may be crucial to understanding MS pathogenesis, and design of lipid antigen-specific therapeutics. Novel immuno-modulatory tools for treatment of autoimmune diseases including MS in which there is both constraint of inflammation and stimulation of remyelination are now emerging.