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Review
. 2020 Jan 15:1727:146532.
doi: 10.1016/j.brainres.2019.146532. Epub 2019 Oct 31.

Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases

Paige B Martin  1 , Amy N Hicks  2 , Sarah E Holbrook  1 , Gregory A Cox  3
Affiliations
Review

Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases

Paige B Martin et al. Brain Res. .

Abstract

Charcot-Marie-Tooth (CMT) disease is a progressive and heterogeneous inherited peripheral neuropathy. A myriad of genetic factors have been identified that contribute to the degeneration of motor and sensory axons in a length-dependent manner. Emerging biological themes underlying disease include defects in axonal trafficking, dysfunction in RNA metabolism and protein homeostasis, as well deficits in the cellular stress response. Moreover, genetic contributions to CMT can have overlap with other neuropathies, motor neuron diseases (MNDs) and neurodegenerative disorders. Recent progress in understanding the molecular biology of CMT and overlapping syndromes aids in the search for necessary therapeutic targets.

Keywords: CMT; Disease spectrum; Genetics; Motor neuron disease; Neurodegeneration; Ribosome-associated quality control.

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Figures

Figure 1.
Figure 1.
Schematic showing that a. genetic contributions can converge onto a similar clinical phenotype as well as a b. genetic contribution presenting with diverging clinical presentation.
Figure 2.
Figure 2.. Mechanisms of disease implicated in CMT and a broader neurodegenerative spectrum.
a. Variants in genes involved in the endo-lysosomal sorting/trafficking, cytoskeleton, and axonal transport can disturb cytoskeletal integrity and impair transportation, limiting the movement of necessary organelles between the cell body and distal portions. b. Disruptions in proteins involved in the processing (CLP1) and charging (AARs proteins) of tRNAs, as well as others can impair translation and RNA metabolism, which slows a high translational demand. Additionally, neomorphic activities of AARs proteins can disrupt neuronal homeostasis. c. Mutations in proteins involved in the rescue and recycling of stalled ribosomes can give rise to potentially toxic polypeptides and disrupts the sensitive cellular economy of neurons and distal axons. d. Impairments in heat shock proteins, chaperones for potentially toxic misfolded proteins, can lead to toxic aggregates that further sequester more heat shock proteins, impairing the appropriate cell stress response.
See this image and copyright information in PMC

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