Modeling ALS and FTLD proteinopathies in yeast: An efficient approach for studying protein aggregation and toxicity

Kryndushkin, Dmitry; Shewmaker, Frank

doi:10.4161/pri.17229

Cited by 25 publications

(25 citation statements)

References 93 publications

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“…In recent years the yeast Saccharomyces cerevisiae has emerged as a very productive eukaryotic system to study heterologous expression of human disease‐related proteins (Winderickx et al ., ; Khurana and Lindquist, ; Kryndushkin and Shewmaker, ). It often recapitulates observations made in higher organisms and offers the possibility for high‐throughput genetic and small‐molecule screening to reveal important information about conserved disease‐related molecular pathways.…”

Section: Introductionmentioning

confidence: 99%

A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity

Kryndushkin

Ihrke

Piermartiri

et al. 2012

Molecular Microbiology

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SummaryMany neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) are linked to the accumulation of specific protein aggregates in affected regions of the nervous system. SOD1, TDP-43, FUS and optineurin (OPTN) proteins were identified to form intraneuronal inclusions in ALS patients. In addition, mutations in OPTN are associated with both ALS and glaucoma. As the pathological role of OPTN in neuronal degeneration remains unresolved, we created a yeast model to study its potential for aggregation and toxicity. We observed that both wild type and diseaseassociated mutants of OPTN form toxic non-amyloid aggregates in yeast. Similar to reported cell culture and mouse models, the OPTN E50K mutant shows enhanced toxicity in yeast, implying a conserved gainof-function mechanism. Furthermore, OPTN shows a unique aggregation pattern compared to other disease-related proteins in yeast. OPTN aggregates colocalize only partially with the insoluble protein deposit (IPOD) site markers, but coincide perfectly with the prion seed-reducing protein Btn2 and several other aggregation-prone proteins, suggesting that protein aggregates are not limited to a single IPOD site. Importantly, changes in the Btn2p level modify OPTN toxicity and aggregation. This study generates a mechanistic framework for investigating how OPTN may trigger pathological changes in ALS and other OPTN-linked neurodegenerative disorders.

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Section: Introductionmentioning

confidence: 99%

A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity

Kryndushkin

Ihrke

Piermartiri

et al. 2012

Molecular Microbiology

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“…One of them, superoxide dismutase 1 (SOD1), has been studied extensively in the context of familial ALS (fALS). Mutant SOD1 tends to aggregate and seems to cause disease via a toxic gain of function mechanism (Kryndushkin and Shewmaker ). Two other proteins, TAR DNA binding protein (TDP‐43) and fused in sarcoma (FUS), are emerging as important disease factors in ALS and FTLD‐U (Neumann ).…”

Section: Protein Misfolding and Aggregation: A Common Feature Among Nmentioning

confidence: 99%

“…In the same manner, disease‐relevant proteins that have no homologs in the yeast genome have been over‐expressed in yeast as fusions to fluorescent proteins, often as a first step to assess their aggregation properties (Outeiro and Lindquist ; Johnson et al . , ; Kryndushkin and Shewmaker ; Kryndushkin et al . , ).…”

Section: Yeast As a Platform To Study Aggregation‐prone Proteins And mentioning

confidence: 99%

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Harnessing the power of yeast to unravel the molecular basis of neurodegeneration

Tenreiro

Munder

Alberti

et al. 2013

Journal of Neurochemistry

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Several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or prion diseases, are known for their intimate association with protein misfolding and aggregation. These disorders are characterized by the loss of specific neuronal populations in the brain and are highly associated with aging, suggesting a decline in proteostasis capacity may contribute to pathogenesis. Nevertheless, the precise molecular mechanisms that lead to the selective demise of neurons remain poorly understood. As a consequence, appropriate therapeutic approaches and effective treatments are largely lacking. The development of cellular and animal models that faithfully reproduce central aspects of neurodegeneration has been crucial for advancing our understanding of these diseases. Approaches involving the sequential use of different model systems, starting with simpler cellular models and ending with validation in more complex animal models, resulted in the discovery of promising therapeutic targets and small molecules with therapeutic potential. Within this framework, the simple and well-characterized eukaryote Saccharomyces cerevisiae, also known as budding yeast, is being increasingly used to study the molecular basis of several neurodegenerative disorders. Yeast provides an unprecedented toolbox for the dissection of complex biological processes and pathways. Here, we summarize how yeast models are adding to our current understanding of several neurodegenerative disorders.

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“…Yeast has proved to be useful in the study of disease-specific proteins that form prion-like aggregates [28][29][30][31][32][33][34][35]. When human proteins associated with aggregation in neurodegenerative disease were expressed in yeast, they formed aggregates and caused toxicity.…”

Section: Introductionmentioning

confidence: 99%

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Park

Watanabe

et al. 2018

Preprint

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Proteins associated with familial neurodegenerative disease often aggregate in patients' neurons.Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets.Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and, like the yeast chromatinremodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN + ] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules which might promote toxic aggregation of CREST. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Down regulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to almost entirely rescue the severe degenerative phenotype induced by human CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases. Author summaryMutations in the calcium-responsive transactivator (CREST) protein have been shown to cause amyotrophic lateral sclerosis (ALS). Here we show that the human CREST protein expressed in yeast forms nuclear aggregates and is toxic. We also show that ATXN2, previously shown to modify ALS toxicity caused by mutations in the TDP-43 encoding gene, also modifies toxicity of CREST expressed in either yeast or flies. These results extend the spectrum of ALS associated proteins affected by ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.

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Modeling ALS and FTLD proteinopathies in yeast: An efficient approach for studying protein aggregation and toxicity

Cited by 25 publications

References 93 publications

A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity

A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity

Harnessing the power of yeast to unravel the molecular basis of neurodegeneration

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

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