Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities

Abstract

Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.

Keywords: Axonal neuropathy; Charcot-Marie-Tooth disease; Pathogenesis; Peripheral neuropathy; Treatment.

Fig. 1

The confluence of axonal neuropathy genes in the regulation of axonal transport, organelle-organelle contacts, and local protein translation. Schematic representation of multiple gene products and associated pathways implicated in inherited axonal neuropathy. (1) Mitofusin 2 (MFN2) regulates mitochondrial axonal transport through recruitment of adaptor proteins and microtubule transport machinery such as kinesin motors. (2) MFN2 regulates mitochondrial-ER contacts. (3) MFN2 regulates mitochondrial tethering and fusion. (4) Rab7 regulates late endosome and lysosome axonal transport and contacts with mitochondria. (5) Rab7-positive late endosomes and lysosomes promote long-range axonal transport of RNA granules and protein translation machinery to support local axonal protein translation. (6) Aminoacyl-tRNA synthetases charge tRNAs to support axonal protein synthesis