Targeting the programmed axon degeneration pathway as a potential therapeutic for Charcot-Marie-Tooth disease

• Published in: Brain research 2020-01, Vol.1727, p.146539-146539, Article 146539
• Main Authors: Moss, Kathryn R., Höke, Ahmet
• Format: Article
• Language: English
• Subjects: Armadillo Domain Proteins - antagonists & inhibitors; Armadillo Domain Proteins - genetics; Axons - metabolism; Axons - pathology; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - therapy; CMT; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - genetics; GARS; Genetic Therapy; HSP; Humans; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - genetics; Molecular Targeted Therapy; MPZ; NAD; Nicotinamide-Nucleotide Adenylyltransferase - antagonists & inhibitors; Nicotinamide-Nucleotide Adenylyltransferase - genetics; NMNAT; Peripheral neuropathy; PMP22; Programmed axon degeneration; SARM1; Therapy development
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2019.146539

•Summary of the programmed axon degeneration pathway.•Review of pathogenesis of CMT subtypes and programmed axon degeneration pathway.•Discussion of therapies based on programmed axon degeneration pathway in CMT. The programmed axon degeneration pathway has emerged as an important process contributing to the pathogenesis of several neurological diseases. The most crucial events in this pathway include activation of the central executioner SARM1 and NAD+ depletion, which leads to an energetic failure and ultimately axon destruction. Given the prevalence of this pathway, it is not surprising that inhibitory therapies are currently being developed in order to treat multiple neurological diseases with the same therapy. Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of neurological diseases that may also benefit from this therapeutic approach. To evaluate the appropriateness of this strategy, the contribution of the programmed axon degeneration pathway to the pathogenesis of different CMT subtypes is being actively investigated. The subtypes CMT1A, CMT1B and CMT2D are the first to have been examined. Based on the results from these studies and advances in developing therapies to block the programmed axon degeneration pathway, promising therapeutics for CMT are now on the horizon.