Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A

Abstract

In Charcot–Marie–Tooth type 1A (CMT1A), Schwann cells exhibit a preponderant transcriptional deficiency of genes involved in lipid biosynthesis. This perturbed lipid metabolism affects the peripheral nerve physiology and the structure of peripheral myelin. Nevertheless, the identification and functional characterization of the lipid species mainly responsible for CMT1A myelin impairment currently lack. This is critical in the pathogenesis of the neuropathy since lipids are many and complex molecules which play essential roles in the cell, including the structural components of cellular membranes, cell signaling, and membrane trafficking. Moreover, lipids themselves are able to modify gene transcription, thereby affecting the genotype–phenotype correlation of well-defined inherited diseases, including CMT1A. Here we report for the first time a comprehensive lipid profiling in experimental and human CMT1A, demonstrating a previously unknown specific alteration of sphingolipid (SP) and glycerophospholipid (GP) metabolism. Notably, SP, and GP changes even emerge in biological fluids of CMT1A rat and human patients, implying a systemic metabolic dysfunction for these specific lipid classes. Actually, SP and GP are not merely reduced; their expression is instead aberrant, contributing to the ultrastructural abnormalities that we detailed by X-ray diffraction in rat and human internode myelin. The modulation of SP and GP pathways in myelinating dorsal root ganglia cultures clearly sustains this issue. In fact, just selected molecules interacting with these pathways are able to modify the altered geometric parameters of CMT1A myelinated fibers. Overall, we propose to exploit the present SP and GP metabolism impairment to select effective drugs and validate a set of reliable biomarkers, which remain a challenge in CMT1A neuropathy.

Metabolic Control of Sensory Neuron Survival by the p75 Neurotrophin Receptor in Schwann Cells

“…Consequently, droplet formation in glia may be an early marker for neurodegeneration. Additionally, while the dynamics of TAG accumulation have not been fully characterized in peripheral nerves, increases in TAG species have been associated with several neuropathies including CMT2, HSN1, CMT1E, and CMT1A (Marshall et al, 2014;Zhou et al, 2019;Giudetti et al, 2020;Visigalli et al, 2020).…”

“…As previously noted in this work, diabetes is the known progenitor of diabetic neuropathy, but only 20-40% of patients with diabetes acquire diabetic neuropathy and both the severity and form of the disease vary greatly in those individuals (M C Perez-Matos, . Additionally, patients with the most common form of CMT, CMT1A, resulting from nearly identical duplications of a chromosomal segment containing the gene encoding peripheral myelin protein 22 (PMP22), have greatly varied phenotypic presentation and progression (Visigalli et al, 2020). This variation suggests that unknown factors, either environmental or genetic, act as modulators in these disorders.…”

“…Especially considering, as previously mentioned, that altered circulating lipid levels are a key risk factor for the development of diabetic neuropathy (M C Perez-Matos, Morales-Alvarez and Mendivil, 2017). Moreover, CMT1A models have recently been shown to have significantly altered lipid metabolism, with widely dysregulated sphingolipid and glycerophospholipid metabolism including aberrant species accumulation (Visigalli et al, 2020).…”

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

“…Diet supplementation with phosphatidylcholine and phosphatidylethanolamine improved myelin biosynthesis and nerve function in this model [ 67 ]. The lipids supplementation approach is further supported by a recent study showing impairments of sphingolipid and glycerophospholipid metabolism in CMT1A [ 118 ]. Although clinical trials showed no side-effects under this treatment [ 68 ], it remains unknown whether high doses of dietary phospholipids can benefit CMT1A patients.…”

Intraepineurial Fat Quantification and Cross-sectional Area Analysis of the Sciatic Nerve Using MRI in Charcot-Marie-Tooth Disease Type 1A Patients

“…10 Studies using a rat model of CMT1A have reported that Schwann cells in this disease exhibit reduced transcription of the genes required for myelin lipid biosynthesis. [11][12][13][14] This perturbed lipid metabolism could be involved in the pathogenesis of the disease by reducing lipid incorporation into myelin, which produces structural changes in the myelin sheath. 11 Moreover, a lipid-enriched diet has been shown to improve myelination in CMT animal models, 11,13 which suggests that exogenous lipid delivery to the peripheral nerves via plasma could potentially affect the myelination of nerve bers in this disease.…”