Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease
Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD,...
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| مؤلفون آخرون: | , , , , , |
| التنسيق: | article |
| منشور في: |
2010
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| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/6142 http://dx.doi.org/10.1002/emmm.201000084 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://embomolmed.embopress.org/content/2/9/349.short |
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| _version_ | 1864513478587318272 |
|---|---|
| author | Sleiman, Sama F. |
| author2 | Mashishi, Lata Coppola, Giovanni Thompson, Leslie M. Ratan, Rajiv R. Starkov, Anatoly Antonyak, Marc A. |
| author2_role | author author author author author author |
| author_facet | Sleiman, Sama F. Mashishi, Lata Coppola, Giovanni Thompson, Leslie M. Ratan, Rajiv R. Starkov, Anatoly Antonyak, Marc A. |
| author_role | author |
| dc.creator.none.fl_str_mv | Sleiman, Sama F. Mashishi, Lata Coppola, Giovanni Thompson, Leslie M. Ratan, Rajiv R. Starkov, Anatoly Antonyak, Marc A. |
| dc.date.none.fl_str_mv | 2010 2017-09-06T08:57:44Z 2017-09-06T08:57:44Z 2017-09-06 |
| dc.identifier.none.fl_str_mv | 1757-4684 http://hdl.handle.net/10725/6142 http://dx.doi.org/10.1002/emmm.201000084 McConoughey, S. J., Basso, M., Niatsetskaya, Z. V., Sleiman, S. F., Smirnova, N. A., Langley, B. C., ... & Li, B. (2010). Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO molecular medicine, 2(9), 349-370. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://embomolmed.embopress.org/content/2/9/349.short |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | EMBO Molecular Medecine |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de‐repressed two established regulators of mitochondrial function, PGC‐1α and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3‐nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC‐independent epigenetic strategy for treating neurodegeneration |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_b0402769a26b0ca8ca75c705ebef90c5 |
| identifier_str_mv | 1757-4684 McConoughey, S. J., Basso, M., Niatsetskaya, Z. V., Sleiman, S. F., Smirnova, N. A., Langley, B. C., ... & Li, B. (2010). Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO molecular medicine, 2(9), 349-370. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/6142 |
| publishDate | 2010 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington diseaseSleiman, Sama F.Mashishi, LataCoppola, GiovanniThompson, Leslie M.Ratan, Rajiv R.Starkov, AnatolyAntonyak, Marc A.Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de‐repressed two established regulators of mitochondrial function, PGC‐1α and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3‐nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC‐independent epigenetic strategy for treating neurodegenerationPublishedN/A2017-09-06T08:57:44Z2017-09-06T08:57:44Z20102017-09-06Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1757-4684http://hdl.handle.net/10725/6142http://dx.doi.org/10.1002/emmm.201000084McConoughey, S. J., Basso, M., Niatsetskaya, Z. V., Sleiman, S. F., Smirnova, N. A., Langley, B. C., ... & Li, B. (2010). Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO molecular medicine, 2(9), 349-370.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttp://embomolmed.embopress.org/content/2/9/349.shortenEMBO Molecular Medecineinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/61422021-03-19T10:00:49Z |
| spellingShingle | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease Sleiman, Sama F. |
| status_str | publishedVersion |
| title | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| title_full | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| title_fullStr | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| title_full_unstemmed | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| title_short | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| title_sort | Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease |
| url | http://hdl.handle.net/10725/6142 http://dx.doi.org/10.1002/emmm.201000084 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://embomolmed.embopress.org/content/2/9/349.short |