Metabolic alterations in Charcot-Marie-Tooth disease type 1A

by Lisa Linhoff
Doctoral thesis
Date of Examination:2021-03-31
Date of issue:2021-05-03
Advisor:Prof. Dr. Michael Werner Sereda
Referee:Prof. Dr. Michael Werner Sereda
Referee:Prof. Dr. Susann Boretius
Persistent Address: http://dx.doi.org/10.53846/goediss-8584

 

 

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Abstract

English

Axo-glia interaction extend beyond myelination itself. Glial cells support axons with metabolites and trophic factors. In numerous disease models, primary glial mutations result in the disturbance of normal nerve conduction. In Charcot-Marie-Tooth disease type 1A (CMT1A), an overexpression of peripheral myelin protein 22 (PMP22) in Schwann cells (SC), the myelinating glial cells of the peripheral nervous system, results in severely reduced nerve conduction velocities and eventually loss of compound muscle action potentials (CMAP) in patients as well as in a rat model (Pmp22tg). Previous studies have reported that reduced axonal numbers and alterations in mRNA expression of the metabolic machinery correlate with disease severity. Recent evidence implicating failed metabolic support in other models of peripheral neuropathies highlight its importance for functional axo-glial interaction. Here, we hypothesize that in CMT1A the challenged SC is no longer able to metabolically support axonal function. In a metabolomics approach complemented with qRT-PCR analysis in nerve lysates of Pmp22tg animals alterations in glucose metabolism were observed. Interestingly, free glucose was enriched while a downregulation of the polyol pathway was observed and no increase of glycogen storages or glycolysis machinery was detected. Glucose transporter1 was increased and localized to Schmidt-Lanterman Incisures as well as the ab- and adaxonal SC surface possibly allowing for the shuttling of free glucose to the axon. We hypothesize that free glucose concentrations fuel the axonal metabolism in peripheral nerves of Pmp22tg animals. Mitochondria of diseased axons showed morphological alterations and adenosine triphosphate (ATP) levels of axons in old Pmp22tg animals decreased as compared to wild type animals. The expression of the mitochondrial gene COX6C detected in blood of CMT1A patients correlated with handgrip strength underlining the importance of mitochondrial alterations in disease pathogenesis. Our data suggest that free glucose is not primarily metabolized in SC, but instead is transported to the axons to meet metabolic demands. During the course of the disease, the increased supply becomes deleterious as a potential axonal glucose overload might drive axonal loss, neuromuscular junction degeneration and muscle atrophy. Understanding the details of axo-glial metabolic coupling in health and its alteration in diseases may promote novel therapeutic targets.
Keywords: Schwann Cells; Peripheral nervous system; CMT1A
 
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