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Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far stu...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409169/ https://www.ncbi.nlm.nih.gov/pubmed/28453524 http://dx.doi.org/10.1371/journal.pone.0175968 |
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author | Coffey, Sydney R. Bragg, Robert M. Minnig, Shawn Ament, Seth A. Cantle, Jeffrey P. Glickenhaus, Anne Shelnut, Daniel Carrillo, José M. Shuttleworth, Dominic D. Rodier, Julie-Anne Noguchi, Kimihiro Bennett, C. Frank Price, Nathan D. Kordasiewicz, Holly B. Carroll, Jeffrey B. |
author_facet | Coffey, Sydney R. Bragg, Robert M. Minnig, Shawn Ament, Seth A. Cantle, Jeffrey P. Glickenhaus, Anne Shelnut, Daniel Carrillo, José M. Shuttleworth, Dominic D. Rodier, Julie-Anne Noguchi, Kimihiro Bennett, C. Frank Price, Nathan D. Kordasiewicz, Holly B. Carroll, Jeffrey B. |
author_sort | Coffey, Sydney R. |
collection | PubMed |
description | Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine Huntingtin gene. To study the relationship between peripheral huntingtin levels and striatal HD phenotypes, we utilized a knock-in model of the human HD mutation (the B6.Htt(Q111/+) mouse). We treated mice with ASOs from 2–10 months of age, a time period over which significant HD-relevant signs progressively develop in the brains of Htt(Q111/+) mice. Peripheral treatment with ASOs led to persistent reduction of huntingtin protein in peripheral organs, including liver (64% knockdown), brown adipose (66% knockdown), and white adipose tissues (71% knockdown). This reduction was not associated with alterations in the severity of HD-relevant signs in the striatum of Htt(Q111/+) mice at the end of the study, including transcriptional dysregulation, the accumulation of neuronal intranuclear inclusions, and behavioral changes such as subtle hypoactivity and reduced exploratory drive. These results suggest that the amount of peripheral reduction achieved in the current study does not significantly impact the progression of HD-relevant signs in the central nervous system. |
format | Online Article Text |
id | pubmed-5409169 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54091692017-05-12 Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease Coffey, Sydney R. Bragg, Robert M. Minnig, Shawn Ament, Seth A. Cantle, Jeffrey P. Glickenhaus, Anne Shelnut, Daniel Carrillo, José M. Shuttleworth, Dominic D. Rodier, Julie-Anne Noguchi, Kimihiro Bennett, C. Frank Price, Nathan D. Kordasiewicz, Holly B. Carroll, Jeffrey B. PLoS One Research Article Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine Huntingtin gene. To study the relationship between peripheral huntingtin levels and striatal HD phenotypes, we utilized a knock-in model of the human HD mutation (the B6.Htt(Q111/+) mouse). We treated mice with ASOs from 2–10 months of age, a time period over which significant HD-relevant signs progressively develop in the brains of Htt(Q111/+) mice. Peripheral treatment with ASOs led to persistent reduction of huntingtin protein in peripheral organs, including liver (64% knockdown), brown adipose (66% knockdown), and white adipose tissues (71% knockdown). This reduction was not associated with alterations in the severity of HD-relevant signs in the striatum of Htt(Q111/+) mice at the end of the study, including transcriptional dysregulation, the accumulation of neuronal intranuclear inclusions, and behavioral changes such as subtle hypoactivity and reduced exploratory drive. These results suggest that the amount of peripheral reduction achieved in the current study does not significantly impact the progression of HD-relevant signs in the central nervous system. Public Library of Science 2017-04-28 /pmc/articles/PMC5409169/ /pubmed/28453524 http://dx.doi.org/10.1371/journal.pone.0175968 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Coffey, Sydney R. Bragg, Robert M. Minnig, Shawn Ament, Seth A. Cantle, Jeffrey P. Glickenhaus, Anne Shelnut, Daniel Carrillo, José M. Shuttleworth, Dominic D. Rodier, Julie-Anne Noguchi, Kimihiro Bennett, C. Frank Price, Nathan D. Kordasiewicz, Holly B. Carroll, Jeffrey B. Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease |
title | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease |
title_full | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease |
title_fullStr | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease |
title_full_unstemmed | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease |
title_short | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.Htt(Q111/+) mouse model of Huntington’s disease |
title_sort | peripheral huntingtin silencing does not ameliorate central signs of disease in the b6.htt(q111/+) mouse model of huntington’s disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409169/ https://www.ncbi.nlm.nih.gov/pubmed/28453524 http://dx.doi.org/10.1371/journal.pone.0175968 |
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