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Updated: May 29, 2026
Characterizing Histone Post-translational Modification Alterations in Yeast Neurodegenerative Proteinopathy Models
Published on: March 24, 2019
Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis
Emma L Bastow1, Campbell W Gourlay, Mick F Tuite
1School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
Abstract:
ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease attributable to the death of motor neurons. Associated with ALS are mutations in the genes encoding SOD1 (superoxide dismutase 1), FUS (fused in Sarcoma) protein and TDP-43 (TAR DNA-binding protein-43) each of which leads to aggregation of the respective protein. For example, the ALS-associated mutations in the hSOD1 (human SOD1) gene typically destabilize the native SOD homodimer, leading to misfolding, aggregation and degradation of SOD1. The ALS-associated pathology is not a consequence of the functional inactivation of SOD1 itself, but is rather due to a toxic gain-of-function triggered by mutant SOD1. Recently, the molecular basis of a number of human neurodegenerative diseases resulting from protein misfolding and aggregation, including fALS (familial ALS), was probed by using the baker's yeast, Saccharomyces cerevisiae, as a highly tractable model. Such studies have, for example, identified novel mutant SOD1-specific interactions and demonstrated that mutant SOD1 disrupts mitochondrial homoeostasis. Features of ALS associated with TDP-43 aggregation have also been recapitulated in S. cerevisiae including the identification of modulators of the toxicity of TDP-43. In this paper, we review recent studies of ALS pathogenesis using S. cerevisiae as a model organism and summarize the potential mechanisms involved in ALS progression.
Insights
Baker's yeast models reveal how mutations in SOD1, FUS, and TDP-43 cause motor neuron death in amyotrophic lateral sclerosis (ALS). These studies uncover toxic protein aggregation mechanisms and mitochondrial dysfunction in ALS pathogenesis.
Area of Science:
- Neurodegenerative diseases
- Molecular biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death.
- Mutations in SOD1, FUS, and TDP-43 genes are linked to ALS, leading to protein misfolding and aggregation.
- Mutant SOD1 triggers a toxic gain-of-function, contributing to ALS pathology.
Purpose of the Study:
- To review recent studies on ALS pathogenesis using Saccharomyces cerevisiae as a model organism.
- To summarize potential mechanisms involved in ALS progression.
- To explore how protein misfolding and aggregation contribute to neurodegeneration.
Main Methods:
- Utilizing baker's yeast (Saccharomyces cerevisiae) as a tractable model system.
- Investigating the molecular basis of human neurodegenerative diseases, including familial ALS (fALS).
- Analyzing protein aggregation and toxicity associated with ALS-related genes (SOD1, FUS, TDP-43).
Main Results:
- Identified novel SOD1-specific interactions in yeast models.
- Demonstrated that mutant SOD1 disrupts mitochondrial homeostasis.
- Recapitulated TDP-43 aggregation features and identified modulators of its toxicity in yeast.
Conclusions:
- Saccharomyces cerevisiae serves as a valuable model for studying ALS pathogenesis.
- Yeast studies provide insights into the mechanisms of toxic protein aggregation and gain-of-function mutations in ALS.
- Further research in yeast models can elucidate pathways involved in motor neuron degeneration.
