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Novel polyglutamine model uncouples proteotoxicity from aging.

Christie NT, Lee AL, Fay HG, Gray AA, Kikis EA - PLoS ONE (2014)

Bottom Line: Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia.In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins.However, surprisingly, this aggregation and resultant toxicity was not influenced by aging.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.

ABSTRACT
Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia. In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins. We are interested in elucidating the underlying mechanisms of toxicity of the protein ataxin-3, in which a polyglutamine expansion is the genetic determinant for Machado-Joseph Disease (MJD), also referred to as spinocerebellar ataxia 3 (SCA3). To this end, we have developed a novel model for ataxin-3 protein aggregation, by expressing a disease-related polyglutamine-containing fragment of ataxin-3 in the genetically tractable body wall muscle cells of the model system C. elegans. Here, we demonstrate that this ataxin-3 fragment aggregates in a polyQ length-dependent manner in C. elegans muscle cells and that this aggregation is associated with cellular dysfunction. However, surprisingly, this aggregation and resultant toxicity was not influenced by aging. This is in contrast to polyglutamine peptides alone whose aggregation/toxicity is highly dependent on age. Thus, the data presented here not only describe a new polyglutamine model, but also suggest that protein context likely influences the cellular interactions of the polyglutamine-containing protein and thereby modulates its toxic properties.

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Effect of aging on AT3CT aggregation.A. Micrographs showing YFP fluorescence in YFP- or AT3CT(Q45 or Q63)-expressing animals. B. Native gels showing the relative distribution of presumptive monomers (m), oligomers (o), and aggregates (a) at day 1 as compared to day 4 of adulthood.
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pone-0096835-g004: Effect of aging on AT3CT aggregation.A. Micrographs showing YFP fluorescence in YFP- or AT3CT(Q45 or Q63)-expressing animals. B. Native gels showing the relative distribution of presumptive monomers (m), oligomers (o), and aggregates (a) at day 1 as compared to day 4 of adulthood.

Mentions: We further asked whether AT3CT(Q45 or Q63) aggregation becomes more pronounced during aging, and/or whether there is a marked increase in oligomer formation during aging. To address this, we first examined the pattern of AT3CT(Q45 or Q63) fluorescence in body wall muscle cells of animals at days 1–4 of adulthood. As shown in Fig. 4A, there was no marked increase in the accumulation of fluorescent foci in either AT3CT(Q45) or AT3CT(Q63). This is in contrast to the observed increase in aggregate formation in transgenic C. elegans expressing a polyQ35 tract alone, fused to YFP, in body wall muscle cells [6]. Additionally, it has been shown that while age-dependent aggregation of AT3CT(Qn) proteins was observed in some neurons, other neurons showed very little aggregation, or very little changes in aggregation during aging [18]. Thus, the apparent lack of age-dependent changes on AT3CT(Qn) aggregation in body wall muscle cells of C. elegans may suggest a cell-type specific effect on the aggregation propensity of these proteins. We further examined the protein content of these AT3CT(Q45 and Q63) animals by native gel analysis and found that even at day 4 of adulthood, there was still an observable amount of monomeric and oligomeric species present in AT3CT(Q45) and oligomeric AT3CT(Q63) (Fig. 4B). This is consistent with the lack of a pronounced increase in AT3CT(Qn) fluorescent foci in body wall muscle cells and indicative of little effect of aging on AT3CT(Q45 or Q63) aggregation.


Novel polyglutamine model uncouples proteotoxicity from aging.

Christie NT, Lee AL, Fay HG, Gray AA, Kikis EA - PLoS ONE (2014)

Effect of aging on AT3CT aggregation.A. Micrographs showing YFP fluorescence in YFP- or AT3CT(Q45 or Q63)-expressing animals. B. Native gels showing the relative distribution of presumptive monomers (m), oligomers (o), and aggregates (a) at day 1 as compared to day 4 of adulthood.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016013&req=5

pone-0096835-g004: Effect of aging on AT3CT aggregation.A. Micrographs showing YFP fluorescence in YFP- or AT3CT(Q45 or Q63)-expressing animals. B. Native gels showing the relative distribution of presumptive monomers (m), oligomers (o), and aggregates (a) at day 1 as compared to day 4 of adulthood.
Mentions: We further asked whether AT3CT(Q45 or Q63) aggregation becomes more pronounced during aging, and/or whether there is a marked increase in oligomer formation during aging. To address this, we first examined the pattern of AT3CT(Q45 or Q63) fluorescence in body wall muscle cells of animals at days 1–4 of adulthood. As shown in Fig. 4A, there was no marked increase in the accumulation of fluorescent foci in either AT3CT(Q45) or AT3CT(Q63). This is in contrast to the observed increase in aggregate formation in transgenic C. elegans expressing a polyQ35 tract alone, fused to YFP, in body wall muscle cells [6]. Additionally, it has been shown that while age-dependent aggregation of AT3CT(Qn) proteins was observed in some neurons, other neurons showed very little aggregation, or very little changes in aggregation during aging [18]. Thus, the apparent lack of age-dependent changes on AT3CT(Qn) aggregation in body wall muscle cells of C. elegans may suggest a cell-type specific effect on the aggregation propensity of these proteins. We further examined the protein content of these AT3CT(Q45 and Q63) animals by native gel analysis and found that even at day 4 of adulthood, there was still an observable amount of monomeric and oligomeric species present in AT3CT(Q45) and oligomeric AT3CT(Q63) (Fig. 4B). This is consistent with the lack of a pronounced increase in AT3CT(Qn) fluorescent foci in body wall muscle cells and indicative of little effect of aging on AT3CT(Q45 or Q63) aggregation.

Bottom Line: Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia.In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins.However, surprisingly, this aggregation and resultant toxicity was not influenced by aging.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.

ABSTRACT
Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia. In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins. We are interested in elucidating the underlying mechanisms of toxicity of the protein ataxin-3, in which a polyglutamine expansion is the genetic determinant for Machado-Joseph Disease (MJD), also referred to as spinocerebellar ataxia 3 (SCA3). To this end, we have developed a novel model for ataxin-3 protein aggregation, by expressing a disease-related polyglutamine-containing fragment of ataxin-3 in the genetically tractable body wall muscle cells of the model system C. elegans. Here, we demonstrate that this ataxin-3 fragment aggregates in a polyQ length-dependent manner in C. elegans muscle cells and that this aggregation is associated with cellular dysfunction. However, surprisingly, this aggregation and resultant toxicity was not influenced by aging. This is in contrast to polyglutamine peptides alone whose aggregation/toxicity is highly dependent on age. Thus, the data presented here not only describe a new polyglutamine model, but also suggest that protein context likely influences the cellular interactions of the polyglutamine-containing protein and thereby modulates its toxic properties.

Show MeSH
Related in: MedlinePlus