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.

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

“…Persistent SGs and deregulated protein aggregation impair cell fitness and aging, contributing to human diseases, including diabetes, cancers, and neurodegenerative diseases [ 35 , 36 ]. Yeasts represent a model complementary to higher eukaryotes for studies of pathophysiology and therapeutic possibilities of neurodegenerative diseases [ 37 , 38 , 39 ]. Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons in the brain and spinal cord.…”

The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis

“…Easy manipulation and availability of high throughput platforms to evaluate the response of yeast cells to directed mutations and drugs strengthen the rationale of using these organisms as disease models, or for testing chemical libraries to find new therapeutic treatments [ 1 , 2 , 3 ]. Saccharomyces cerevisiae , Candida albicans, or Schizosaccharomyces pombe [ 4 ] have been traditionally used with this purpose or as cell factories, but there are many other yeasts that could be also included as far as the knowledge of their biology and regulatory molecular mechanisms controlling principal functions would increase.…”

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease

“…Until now, various models such as rodents, the zebrafish, fruit fly, yeast, cell lines and induced pluripotent stem cells (iPSCs) have been developed for CMT modeling [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Rodent CMT models have advanced understanding of neuropathy; however, regarding MFN2 of CMT2A, which is the most frequent subtype of axonal CMT, it used to be difficult to reproduce the phenotype in rodent due to embryonic lethality [ 58 ].…”