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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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Related in: MedlinePlus

The toxic effects of AT3CT expression in C. elegans body wall muscle cells.Motility was determined as a measure of thrashing rate in liquid for L4 larvae (A) or animals at day 4 of adulthood (B). All 30 individual data points are represented on a dot blot. The symbol “▪” represents means. 95 percent confidence intervals are indicated. P-values are the results of pairwise student t-test.
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pone-0096835-g003: The toxic effects of AT3CT expression in C. elegans body wall muscle cells.Motility was determined as a measure of thrashing rate in liquid for L4 larvae (A) or animals at day 4 of adulthood (B). All 30 individual data points are represented on a dot blot. The symbol “▪” represents means. 95 percent confidence intervals are indicated. P-values are the results of pairwise student t-test.

Mentions: The finding described above, namely that both AT3CT(Q45) and AT3CT(Q63) proteins formed a detectable amount of oligomeric species, and the fact that AT3 with an expanded polyQ tract is the determinant for MJD, led us to ask whether these proteins have toxic effects in C. elegans body wall muscle cells. To address this, we monitored the ability of N2 (wild type), YFP-expressing, or AT3CT(Q45 or Q63)-expressing L4 larval stage animals to thrash in liquid, a movement that is dependent on body wall muscle cell function. Consistent with previous findings in neurons [18], the expression of AT3CT protein in body wall muscle cells significantly reduced thrashing rate (Fig. 3A). Specifically, while the expression of YFP alone in body wall muscle cells impaired the ability of the animals to thrash in liquid as compared to wild type, an even more significant reduction in motor function was observed in animals expressing AT3CT(Q45 or Q63). The mean thrashing rate for YFP-expressing animals was 143 thrashes/min, whereas the mean for AT3CT(Q45) was 121 thrashes/min and 94 thrashes/min for AT3CT(Q63). Individual data points for each of 30 animals measured for each of the four genotypes (N2, YFP, AT3CT(Q45), and AT3CT(Q63)) are shown in Fig. 3A to indicate the full range of data.


Novel polyglutamine model uncouples proteotoxicity from aging.

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

The toxic effects of AT3CT expression in C. elegans body wall muscle cells.Motility was determined as a measure of thrashing rate in liquid for L4 larvae (A) or animals at day 4 of adulthood (B). All 30 individual data points are represented on a dot blot. The symbol “▪” represents means. 95 percent confidence intervals are indicated. P-values are the results of pairwise student t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0096835-g003: The toxic effects of AT3CT expression in C. elegans body wall muscle cells.Motility was determined as a measure of thrashing rate in liquid for L4 larvae (A) or animals at day 4 of adulthood (B). All 30 individual data points are represented on a dot blot. The symbol “▪” represents means. 95 percent confidence intervals are indicated. P-values are the results of pairwise student t-test.
Mentions: The finding described above, namely that both AT3CT(Q45) and AT3CT(Q63) proteins formed a detectable amount of oligomeric species, and the fact that AT3 with an expanded polyQ tract is the determinant for MJD, led us to ask whether these proteins have toxic effects in C. elegans body wall muscle cells. To address this, we monitored the ability of N2 (wild type), YFP-expressing, or AT3CT(Q45 or Q63)-expressing L4 larval stage animals to thrash in liquid, a movement that is dependent on body wall muscle cell function. Consistent with previous findings in neurons [18], the expression of AT3CT protein in body wall muscle cells significantly reduced thrashing rate (Fig. 3A). Specifically, while the expression of YFP alone in body wall muscle cells impaired the ability of the animals to thrash in liquid as compared to wild type, an even more significant reduction in motor function was observed in animals expressing AT3CT(Q45 or Q63). The mean thrashing rate for YFP-expressing animals was 143 thrashes/min, whereas the mean for AT3CT(Q45) was 121 thrashes/min and 94 thrashes/min for AT3CT(Q63). Individual data points for each of 30 animals measured for each of the four genotypes (N2, YFP, AT3CT(Q45), and AT3CT(Q63)) are shown in Fig. 3A to indicate the full range of data.

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