Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease
Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin p...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/79814 https://orcid.org/0000-0002-0524-5301 https://orcid.org/0000-0001-5016-0756 |
| _version_ | 1811093278594957312 |
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| author | Sathasivam, Kirupa Neueder, Andreas Landles, Christian Benjamin, Agnesska C. Bondulich, Marie K. Amith, Donna L. Faull, Richard L. M. Roos, Raymund A. C. Howland, David Detloff, Peter J. Bates, Gillian P. Housman, David E Wasylenko, Theresa Anne |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Sathasivam, Kirupa Neueder, Andreas Landles, Christian Benjamin, Agnesska C. Bondulich, Marie K. Amith, Donna L. Faull, Richard L. M. Roos, Raymund A. C. Howland, David Detloff, Peter J. Bates, Gillian P. Housman, David E Wasylenko, Theresa Anne |
| author_sort | Sathasivam, Kirupa |
| collection | MIT |
| description | Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length–dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings. |
| first_indexed | 2024-09-23T15:42:24Z |
| format | Article |
| id | mit-1721.1/79814 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:42:24Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/798142022-10-02T03:32:48Z Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease Sathasivam, Kirupa Neueder, Andreas Landles, Christian Benjamin, Agnesska C. Bondulich, Marie K. Amith, Donna L. Faull, Richard L. M. Roos, Raymund A. C. Howland, David Detloff, Peter J. Bates, Gillian P. Housman, David E Wasylenko, Theresa Anne Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Gipson, Theresa Anne Housman, David E. Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length–dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings. Cure Huntington’s Disease Initiative, Inc. 2013-08-08T18:48:24Z 2013-08-08T18:48:24Z 2013-01 2012-12 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/79814 Sathasivam, K., A. Neueder, T. A. Gipson, C. Landles, A. C. Benjamin, M. K. Bondulich, D. L. Smith, et al. “Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease.” Proceedings of the National Academy of Sciences 110, no. 6 (February 5, 2013): 2366-2370. https://orcid.org/0000-0002-0524-5301 https://orcid.org/0000-0001-5016-0756 en_US http://dx.doi.org/10.1073/pnas.1221891110 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Sathasivam, Kirupa Neueder, Andreas Landles, Christian Benjamin, Agnesska C. Bondulich, Marie K. Amith, Donna L. Faull, Richard L. M. Roos, Raymund A. C. Howland, David Detloff, Peter J. Bates, Gillian P. Housman, David E Wasylenko, Theresa Anne Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease |
| title | Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease |
| title_full | Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease |
| title_fullStr | Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease |
| title_full_unstemmed | Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease |
| title_short | Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease |
| title_sort | aberrant splicing of htt generates the pathogenic exon 1 protein in huntington disease |
| url | http://hdl.handle.net/1721.1/79814 https://orcid.org/0000-0002-0524-5301 https://orcid.org/0000-0001-5016-0756 |
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