ALS Yeast Models—Past Success Stories and New Opportunities

Gregorio, Sonja E. Di; Duennwald, Martin L.

doi:10.3389/fnmol.2018.00394

Cited by 19 publications

(18 citation statements)

References 151 publications

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“…To explore RGNEF, we established a novel yeast model. Similar studies in yeast have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with both normal cell function and disease, especially neurodegenerative disorders, such as ALS [ 44 , 45 , 46 , 47 , 48 ]. Compared to most other known ALS proteins, RGNEF is relatively understudied, possibly because RGNEF is challenging to explore as it is a large complex protein with many functional domains and extremely difficult to clone, express and purify.…”

Section: Discussionmentioning

confidence: 99%

Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network

Gregorio

Volkening

Strong

et al. 2020

IJMS

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The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in ARHGEF28 has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein. Little is known about the normal biological function of RGNEF or how it contributes to ALS pathogenesis. To further explore RGNEF biology we have established and characterized a yeast model and characterized RGNEF expression in several mammalian cell lines. We demonstrate that RGNEF is toxic when overexpressed and forms inclusions. We also found that the fALS-associated mutation in ARGHEF28 gives rise to an inclusion-forming and toxic protein. Additionally, through unbiased screening using the split-ubiquitin system, we have identified RGNEF-interacting proteins, including two ALS-associated proteins. Functional characterization of other RGNEF interactors identified in our screen suggest that RGNEF functions as a microtubule regulator. Our findings indicate that RGNEF misfolding and toxicity may cause impairment of the microtubule network and contribute to ALS pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network

Gregorio

Volkening

Strong

et al. 2020

IJMS

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“…These models demonstrate the great potential of yeast as a tool to find relevant genes and understand the biological pathways that are involved in ALS pathology, as well as to identify potential therapeutic leads (Figley and Gitler, 2013; Shrestha and Megeney, 2015; Di Gregorio and Duennwald, 2018).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 95%

“…More than ten yeast models expressing different ALS-associated proteins have been established (Damme et al, 2017; Di Gregorio and Duennwald, 2018). The established yeast models include exogenically-expressed mutations in genes involved in RNA metabolism and protein misfolding, such as TAR DNA binding Protein 43 (TDP-43) and fused in sarcoma (FUS), as well as superoxide dismutase 1 (SOD1) (Bastow et al, 2011).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

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Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy

Rencus‐Lazar

DeRowe

Adsi

et al. 2019

Front. Mol. Biosci.

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First described almost two decades ago, the pioneering yeast models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, have become well-established research tools, providing both basic mechanistic insights as well as a platform for the development of therapeutic agents. These maladies are associated with the formation of aggregative amyloid protein structures showing common characteristics, such as the assembly of soluble oligomeric species, binding of indicative dyes, and apoptotic cytotoxicity. The canonical yeast models have recently been expanded by the establishment of a model for type II diabetes, a non-neurological amyloid-associated disease. While these model systems require the exogenous expression of mammalian proteins in yeast, an additional amyloid-associated disease model, comprising solely mutations of endogenous yeast genes, has been recently described. Mutated in the adenine salvage pathway, this yeast model exhibits adenine accumulation, thereby recapitulating adenine inborn error of metabolism disorders. Moreover, in line with the recent extension of the amyloid hypothesis to include metabolite amyloids, in addition to protein-associated ones, the intracellular assembly of adenine amyloid-like structures has been demonstrated using this yeast model. In this review, we describe currently available yeast models of diverse amyloid-associated disorders, as well as their impact on our understanding of disease mechanisms and contribution to future potential drug development.

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“…Despite unicellular models not being able to recapitulate complex disease phenotypes for certain, the completely sequenced genome [ 86 ] and the presence of an ortholog for many human disease genes [ 87 ] render the eukaryote budding yeast Saccharomyces cerevisiae a good candidate for where to model different pathologies [ 88 , 89 , 90 ]. As such, this model organism has been used to set up pioneering experiments identifying several different ALS genetic modifiers.…”

Section: Modeling Als In Different Systemsmentioning

confidence: 99%

Where and Why Modeling Amyotrophic Lateral Sclerosis

Liguori

Amadio

Volonté

2021

IJMS

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Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS.

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ALS Yeast Models—Past Success Stories and New Opportunities

Cited by 19 publications

References 151 publications

Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network

Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network

Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy

Where and Why Modeling Amyotrophic Lateral Sclerosis

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