A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

Abstract

Charcot-Marie-Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.

Keywords: Charcot-Marie-Tooth disease; neurodegenerative diseases; neuropathy; yeast model organism.

Figure 1

Scheme showing the localization of selected proteins, in which mutations have been associated with hereditary peripheral neuropathies in a human nerve cell and a yeast Saccharomyces cerevisiae cell. The violet color indicates human proteins complementing mutations in yeast proteins, marked in red; green indicates human proteins possessing orthologs in yeast S. cerevisiae that are marked orange.

Figure 2

Yeast as a system to evaluate functional effects of human genetic variations. The coding part of a human gene (cDNA) is inserted under a yeast regulatory sequence and transformed into yeast cells, where it is expressed. The resulting protein interacts with yeast cellular components (proteins, RNAs, lipids, etc.) and affects the cell physiology, leading to the selected phenotypes which may be monitored. The system presented may be used to test unknown sequence variants to improve diagnosis, or for screening drug candidates and investigating the molecular mechanisms of pathogenicity to develop future experimental therapies.