Applicability of Yeast Genetics to Neurologic Disease

Abstract

As advances in gene mapping technology reveal genes associated with neurologic diseases, the need to identify a gene's normal function arises often. Experimental genetics is very useful in identifying a gene's function. It relies on model organisms both because it is not appropriate in humans, and because many processes are remarkably similar among eukaryotes. Many cellular processes have evolved once, and species differences are variations on a theme. Molecular genetic tools available in the yeast Saccharomyces cerevisiae provide a means to more rapidly reach an understanding of gene function, yielding substantial insight into the same process in humans. Yeast will never complain of headache or "spells," but do have expansions of trinucleotide repeats, prions, and other processes very much analogous to those underlying many neurologic diseases. In spite of the absence of a nervous system in yeast, yeast genetics has contributed substantial insight into neurologic diseases mechanisms. The real strength of yeast in studying human disease is in genetic analysis of gene function and in providing genetically powerful functional assays. Arch Neurol. 2000;57:1129-1134

A novel high-throughput yeast genetic screen for factors modifying protein levels of the Early-Onset Torsion Dystonia-associated variant torsinAΔE

“…Sixty percent of yeast genes are homologous to human genes, and the use of yeast as a model organism to study mammalian cell biology in health and disease has uncovered invaluable information with high therapeutic relevance ( Karathia et al, 2011 ; Botstein and Fink, 2011 ). In fact, conserved factors involved in amyotrophic lateral sclerosis, mitochondrial disorders, α-antitrypsin deficiency, prion diseases, CDGs, cystic fibrosis, kidney diseases, cancer, and Alzheimer's, Parkinson's, and Huntington's diseases, among many others, have been identified using yeast ( Walberg, 2000 ; Winderickx et al, 2008 ; Bharadwaj et al, 2010 ; Kryndushkin and Shewmaker, 2011 ; Sarto-Jackson and Tomaska, 2016 ; Willingham et al, 2003 ; Giorgini et al, 2005 ; Youker et al, 2004 ). Given the past success of our yeast system in identifying relevant factors involved in torsinA and torsinAΔE biogenesis ( Zacchi et al, 2014 ), and the demonstrated efficacy of yeast as a model organism, we anticipate that many of the genes identified in our screen will prove relevant in mammalian cells.…”

A novel high-throughput yeast genetic screen for factors modifying protein levels of the Early-Onset Torsion Dystonia-associated variant torsinAΔE

“…Sixty percent of yeast genes are homologous to human genes, and the use of yeast as a model organism to study mammalian cell biology in health and disease has uncovered invaluable information with high therapeutic relevance ( Karathia et al, 2011 ; Botstein and Fink, 2011 ). In fact, conserved factors involved in amyotrophic lateral sclerosis, mitochondrial disorders, α-antitrypsin deficiency, prion diseases, CDGs, cystic fibrosis, kidney diseases, cancer, and Alzheimer's, Parkinson's, and Huntington's diseases, among many others, have been identified using yeast ( Walberg, 2000 ; Winderickx et al, 2008 ; Bharadwaj et al, 2010 ; Kryndushkin and Shewmaker, 2011 ; Sarto-Jackson and Tomaska, 2016 ; Willingham et al, 2003 ; Giorgini et al, 2005 ; Youker et al, 2004 ). Given the past success of our yeast system in identifying relevant factors involved in torsinA and torsinAΔE biogenesis ( Zacchi et al, 2014 ), and the demonstrated efficacy of yeast as a model organism, we anticipate that many of the genes identified in our screen will prove relevant in mammalian cells.…”

Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research

“…Furthermore, it is easy to cultivate and maintain in large population size in the laboratory. In addition, two-thirds of all yeast genes share at least one domain of significant homology with human genes, and about 30% of known genes involved in human diseases have yeast orthologs [ 72 ].…”

“…S. cerevisiae exhibits high meiotic recombination rates, with an average of about 90 crossovers per meiosis, allowing precise quantitative phenotyping [ 71 , 73 , 74 ]. The homologous recombination in yeast is highly efficient, facilitating the deletion of sequences or genes in vivo [ 72 , 75 ]. This efficient recombination permitted the generation of the first complete deletion mutant strain collection using gene replacement with the G418 resistance gene (KanMX) cassette in the reference S. cerevisiae strain [ 76 ].…”

Mitochondrial involvement in cell death of non-mammalian eukaryotes

“…Exploitation of yeast as a model system has laid the groundwork for subsequent work on a wide range of human disease genes related to mitochondrial disorders [183, 184], metabolic disorders [185–187], aging [188, 189], neurodegeneration [190, 191], and cancer [192], often leading to major new lines of research. Perhaps the most unexpected application of yeast genetics is in the study of neurodegeneration, where yeast have contributed importantly to our understanding of the mechanisms of protein misfolding and aggregation common to Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD) [193–195].…”

A novel high-throughput yeast genetic screen for factors modifying protein levels of the Early-Onset Torsion Dystonia-associated variant torsinAΔE

“…Sixty percent of yeast genes are homologous to human genes, and the use of yeast as a model organism to study mammalian cell biology in health and disease has uncovered invaluable information with high therapeutic relevance ( Karathia et al, 2011 ; Botstein and Fink, 2011 ). In fact, conserved factors involved in amyotrophic lateral sclerosis, mitochondrial disorders, α-antitrypsin deficiency, prion diseases, CDGs, cystic fibrosis, kidney diseases, cancer, and Alzheimer's, Parkinson's, and Huntington's diseases, among many others, have been identified using yeast ( Walberg, 2000 ; Winderickx et al, 2008 ; Bharadwaj et al, 2010 ; Kryndushkin and Shewmaker, 2011 ; Sarto-Jackson and Tomaska, 2016 ; Willingham et al, 2003 ; Giorgini et al, 2005 ; Youker et al, 2004 ). Given the past success of our yeast system in identifying relevant factors involved in torsinA and torsinAΔE biogenesis ( Zacchi et al, 2014 ), and the demonstrated efficacy of yeast as a model organism, we anticipate that many of the genes identified in our screen will prove relevant in mammalian cells.…”

Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research

“…Furthermore, it is easy to cultivate and maintain in large population size in the laboratory. In addition, two-thirds of all yeast genes share at least one domain of significant homology with human genes, and about 30% of known genes involved in human diseases have yeast orthologs [ 72 ].…”

“…S. cerevisiae exhibits high meiotic recombination rates, with an average of about 90 crossovers per meiosis, allowing precise quantitative phenotyping [ 71 , 73 , 74 ]. The homologous recombination in yeast is highly efficient, facilitating the deletion of sequences or genes in vivo [ 72 , 75 ]. This efficient recombination permitted the generation of the first complete deletion mutant strain collection using gene replacement with the G418 resistance gene (KanMX) cassette in the reference S. cerevisiae strain [ 76 ].…”

Mitochondrial involvement in cell death of non-mammalian eukaryotes

“…Exploitation of yeast as a model system has laid the groundwork for subsequent work on a wide range of human disease genes related to mitochondrial disorders [183, 184], metabolic disorders [185–187], aging [188, 189], neurodegeneration [190, 191], and cancer [192], often leading to major new lines of research. Perhaps the most unexpected application of yeast genetics is in the study of neurodegeneration, where yeast have contributed importantly to our understanding of the mechanisms of protein misfolding and aggregation common to Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD) [193–195].…”

A novel high-throughput yeast genetic screen for factors modifying protein levels of the Early-Onset Torsion Dystonia-associated variant torsinAΔE

“…Sixty percent of yeast genes are homologous to human genes, and the use of yeast as a model organism to study mammalian cell biology in health and disease has uncovered invaluable information with high therapeutic relevance ( Karathia et al, 2011 ; Botstein and Fink, 2011 ). In fact, conserved factors involved in amyotrophic lateral sclerosis, mitochondrial disorders, α-antitrypsin deficiency, prion diseases, CDGs, cystic fibrosis, kidney diseases, cancer, and Alzheimer's, Parkinson's, and Huntington's diseases, among many others, have been identified using yeast ( Walberg, 2000 ; Winderickx et al, 2008 ; Bharadwaj et al, 2010 ; Kryndushkin and Shewmaker, 2011 ; Sarto-Jackson and Tomaska, 2016 ; Willingham et al, 2003 ; Giorgini et al, 2005 ; Youker et al, 2004 ). Given the past success of our yeast system in identifying relevant factors involved in torsinA and torsinAΔE biogenesis ( Zacchi et al, 2014 ), and the demonstrated efficacy of yeast as a model organism, we anticipate that many of the genes identified in our screen will prove relevant in mammalian cells.…”

Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research

“…Furthermore, it is easy to cultivate and maintain in large population size in the laboratory. In addition, two-thirds of all yeast genes share at least one domain of significant homology with human genes, and about 30% of known genes involved in human diseases have yeast orthologs [ 72 ].…”

“…S. cerevisiae exhibits high meiotic recombination rates, with an average of about 90 crossovers per meiosis, allowing precise quantitative phenotyping [ 71 , 73 , 74 ]. The homologous recombination in yeast is highly efficient, facilitating the deletion of sequences or genes in vivo [ 72 , 75 ]. This efficient recombination permitted the generation of the first complete deletion mutant strain collection using gene replacement with the G418 resistance gene (KanMX) cassette in the reference S. cerevisiae strain [ 76 ].…”

Mitochondrial involvement in cell death of non-mammalian eukaryotes

“…Exploitation of yeast as a model system has laid the groundwork for subsequent work on a wide range of human disease genes related to mitochondrial disorders [183, 184], metabolic disorders [185–187], aging [188, 189], neurodegeneration [190, 191], and cancer [192], often leading to major new lines of research. Perhaps the most unexpected application of yeast genetics is in the study of neurodegeneration, where yeast have contributed importantly to our understanding of the mechanisms of protein misfolding and aggregation common to Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD) [193–195].…”