Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.
There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase...
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| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003781&type=printable |
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| author | Mimi Cushman-Nick Nancy M Bonini James Shorter |
| author_facet | Mimi Cushman-Nick Nancy M Bonini James Shorter |
| author_sort | Mimi Cushman-Nick |
| collection | DOAJ |
| description | There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression. |
| format | Article |
| id | doaj-art-0b4f9a5a2d19483cbf756cbae6d97219 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-0b4f9a5a2d19483cbf756cbae6d972192025-01-16T05:31:15ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-0199e100378110.1371/journal.pgen.1003781Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.Mimi Cushman-NickNancy M BoniniJames ShorterThere are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003781&type=printable |
| spellingShingle | Mimi Cushman-Nick Nancy M Bonini James Shorter Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. PLoS Genetics |
| title | Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. |
| title_full | Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. |
| title_fullStr | Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. |
| title_full_unstemmed | Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. |
| title_short | Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model. |
| title_sort | hsp104 suppresses polyglutamine induced degeneration post onset in a drosophila mjd sca3 model |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003781&type=printable |
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