Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ 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 fa...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0175968&type=printable |
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| author | Sydney R Coffey Robert M Bragg Shawn Minnig Seth A Ament Jeffrey P Cantle Anne Glickenhaus Daniel Shelnut José M Carrillo Dominic D Shuttleworth Julie-Anne Rodier Kimihiro Noguchi C Frank Bennett Nathan D Price Holly B Kordasiewicz Jeffrey B Carroll |
| author_facet | Sydney R Coffey Robert M Bragg Shawn Minnig Seth A Ament Jeffrey P Cantle Anne Glickenhaus Daniel Shelnut José M Carrillo Dominic D Shuttleworth Julie-Anne Rodier Kimihiro Noguchi C Frank Bennett Nathan D Price Holly B Kordasiewicz Jeffrey B Carroll |
| author_sort | Sydney R Coffey |
| collection | DOAJ |
| 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.HttQ111/+ 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 HttQ111/+ 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 HttQ111/+ 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 | Article |
| id | doaj-art-51be1c48c7b241a8b7a44ebe739c65ac |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-51be1c48c7b241a8b7a44ebe739c65ac2025-01-16T05:31:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01124e017596810.1371/journal.pone.0175968Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease.Sydney R CoffeyRobert M BraggShawn MinnigSeth A AmentJeffrey P CantleAnne GlickenhausDaniel ShelnutJosé M CarrilloDominic D ShuttleworthJulie-Anne RodierKimihiro NoguchiC Frank BennettNathan D PriceHolly B KordasiewiczJeffrey B CarrollHuntington'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.HttQ111/+ 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 HttQ111/+ 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 HttQ111/+ 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0175968&type=printable |
| spellingShingle | Sydney R Coffey Robert M Bragg Shawn Minnig Seth A Ament Jeffrey P Cantle Anne Glickenhaus Daniel Shelnut José M Carrillo Dominic D Shuttleworth Julie-Anne Rodier Kimihiro Noguchi C Frank Bennett Nathan D Price Holly B Kordasiewicz Jeffrey B Carroll Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. PLoS ONE |
| title | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. |
| title_full | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. |
| title_fullStr | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. |
| title_full_unstemmed | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. |
| title_short | Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. |
| title_sort | peripheral huntingtin silencing does not ameliorate central signs of disease in the b6 httq111 mouse model of huntington s disease |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0175968&type=printable |
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