Flanking sequences profoundly alter polyglutamine toxicity in yeast

Duennwald, Martin L.; Jagadish, S.; Muchowski, Paul J.; Lindquist, Susan

doi:10.1073/pnas.0604547103

Cited by 268 publications

(362 citation statements)

References 57 publications

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“…ThT has an emission spectrum that is red-shifted upon amyloid-binding, therefore allowing co-localization with aggregation-prone Interestingly, toxic and non-toxic aggregates of glutamine-expanded huntingtin have distinct subcellular aggregation patterns. Toxic huntingtin forms multiple punctuate foci, whereas the non-toxic structural variant is present in a single cytosolic focus (Duennwald et al 2006a;Duennwald et al 2006b). …”

Section: Fluorescence Microscopy and Staining Of Amyloid-like Aggregatesmentioning

confidence: 99%

Biochemical, Cell Biological, and Genetic Assays to Analyze Amyloid and Prion Aggregation in Yeast

Alberti

Halfmann

Lindquist

2010

Methods in Enzymology

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Section: Fluorescence Microscopy and Staining Of Amyloid-like Aggregatesmentioning

confidence: 99%

Biochemical, Cell Biological, and Genetic Assays to Analyze Amyloid and Prion Aggregation in Yeast

Alberti

Halfmann

Lindquist

2010

Methods in Enzymology

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“…The yeast models expressing a fragment of the human polyQ protein huntingtin (htt), htt exon I, recapitulate major features of proteins with polyQ expansions including their graded, polyQ length-dependent aggregation and toxicity (13). The yeast system offers the unique opportunity to dissect modulators of polyQ toxicity in a defined and uniform cellular environment.…”

mentioning

confidence: 99%

“…In addition, the numerous genetic tools available in yeast make it a powerful instrument to explore the intramolecular and intermolecular factors that govern polyQ toxicity. In our companion article (13) we investigated the effects of flanking amino acid sequences on polyQ toxicity. Here we explore the impact of protein-protein interactions on polyQ toxicity.…”

mentioning

confidence: 99%

“…In our companion article, which provides background information crucial for the understanding of this article, we explored the effects of short amino acid sequences that have strong consequences on the toxicity of a polyQ-expanded htt exon I protein when present on the same polypeptide chain (13). A FLAG epitope can convert an otherwise benign polyQ protein into a toxic one.…”

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confidence: 99%

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A network of protein interactions determines polyglutamine toxicity

Duennwald

Jagadish

Giorgini

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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146

193

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Several neurodegenerative diseases are associated with the toxicity of misfolded proteins. This toxicity must arise from a combination of the amino acid sequences of the misfolded proteins and their interactions with other factors in their environment. A particularly compelling example of how profoundly these intramolecular and intermolecular factors can modulate the toxicity of a misfolded protein is provided by the polyglutamine (polyQ) diseases. All of these disorders are caused by glutamine expansions in proteins that are broadly expressed, yet the nature of the proteins that harbor the glutamine expansions and the particular pathologies they produce are very different. We find, using a yeast model, that amino acid sequences that modulate polyQ toxicity in cis can also do so in trans. Furthermore, the prion conformation of the yeast protein Rnq1 and the level of expression of a suite of other glutamine-rich proteins profoundly affect polyQ toxicity. They can convert polyQ expansion proteins from toxic to benign and vice versa. Our work presents a paradigm for how a complex, dynamic interplay between intramolecular features of polyQ proteins and intermolecular factors in the cellular environment might determine the unique pathobiologies of polyQ expansion proteins.huntingtin ͉ Huntington's disease ͉ protein misfolding ͉ yeast A variety of human diseases are characterized by the accumulation of aggregated, misfolded proteins (1, 2). In some cases, such as cystic fibrosis, disease is caused by the loss of a vital protein function due simply to this misfolding and aggregation. In other cases, however, protein misfolding creates novel, toxic properties. For example, in Alzheimer's disease, Parkinson's disease, and the polyglutamine (polyQ) disorders, misfolded proteins disrupt proper cellular function and cause cytotoxicity (3,4). In all of these diseases the amino acid sequences of the particular misfolded protein and their interactions determined by its specific environment must govern toxicity. Yet, despite intense research, we know little about these intramolecular and intermolecular factors. Without identifying and understanding these factors at a molecular level it will be difficult to devise the most effective therapeutic strategies to treat protein misfolding diseases.The polyQ diseases present a promising starting point to study this very general problem. In all of these diseases polyQ expansions constitute the molecular basis of disease (5). However, the disease pathologies (including the cell types most strongly affected) and the individual proteins that bear the disease-causing polyQ expansions are very distinct (5). Consequently, the amino acids flanking the polyQ region and the sets of cellular factors that specifically interact with each polyQ expansion protein are different. Combinations of these factors must account for their different pathobiologies. Recent studies have started to identify protein-protein and genetic interaction networks for polyQ proteins (6-8), but the current data do not yet ...

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“…PLA pathogenesis. Flanking peptide sequences were shown to be critical for the toxicity of poly-Q expansions in HD (Duennwald et al, 2006). Further studies are needed to test the same possibility in DRPLA.…”

Section: Discussionmentioning

confidence: 99%

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

Ying

Zhuang

et al. 2009

Developmental Dynamics

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wildtype Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins.

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Flanking sequences profoundly alter polyglutamine toxicity in yeast

Cited by 268 publications

References 57 publications

Biochemical, Cell Biological, and Genetic Assays to Analyze Amyloid and Prion Aggregation in Yeast

Biochemical, Cell Biological, and Genetic Assays to Analyze Amyloid and Prion Aggregation in Yeast

A network of protein interactions determines polyglutamine toxicity

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

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