Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice.
Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates...
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3633920?pdf=render |
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| author | Huu Phuc Nguyen Jeannette Hübener Jonasz Jeremiasz Weber Stephan Grueninger Olaf Riess Andreas Weiss |
| author_facet | Huu Phuc Nguyen Jeannette Hübener Jonasz Jeremiasz Weber Stephan Grueninger Olaf Riess Andreas Weiss |
| author_sort | Huu Phuc Nguyen |
| collection | DOAJ |
| description | Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Förster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis. |
| first_indexed | 2024-04-13T20:03:17Z |
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| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T20:03:17Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-af7c6bade86045dbbdeae5a70561c91e2022-12-22T02:32:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0184e6204310.1371/journal.pone.0062043Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice.Huu Phuc NguyenJeannette HübenerJonasz Jeremiasz WeberStephan GrueningerOlaf RiessAndreas WeissSpinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Förster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis.http://europepmc.org/articles/PMC3633920?pdf=render |
| spellingShingle | Huu Phuc Nguyen Jeannette Hübener Jonasz Jeremiasz Weber Stephan Grueninger Olaf Riess Andreas Weiss Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. PLoS ONE |
| title | Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. |
| title_full | Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. |
| title_fullStr | Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. |
| title_full_unstemmed | Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. |
| title_short | Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. |
| title_sort | cerebellar soluble mutant ataxin 3 level decreases during disease progression in spinocerebellar ataxia type 3 mice |
| url | http://europepmc.org/articles/PMC3633920?pdf=render |
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