Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics,...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2006-02-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996105002160 |
| _version_ | 1818560391282688000 |
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| author | Yuji Tanaka Shuichi Igarashi Masayuki Nakamura Juliette Gafni Cameron Torcassi Gabrielle Schilling Danielle Crippen Jonathan D. Wood Akira Sawa Nancy A. Jenkins Neal G. Copeland David R. Borchelt Christopher A. Ross Lisa M. Ellerby |
| author_facet | Yuji Tanaka Shuichi Igarashi Masayuki Nakamura Juliette Gafni Cameron Torcassi Gabrielle Schilling Danielle Crippen Jonathan D. Wood Akira Sawa Nancy A. Jenkins Neal G. Copeland David R. Borchelt Christopher A. Ross Lisa M. Ellerby |
| author_sort | Yuji Tanaka |
| collection | DOAJ |
| description | Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics, we have generated a new inducible mouse model of HD expressing full-length huntingtin (Htt) using a tetracycline-regulated promoter. In double transgenic mice Htt was expressed widely in the brain under the control of the tet-transactivator (tTA) driven by the prion promoter PrP (in the absence of doxycycline). Mice expressing full-length mutant Htt, but not full-length normal Htt, displayed a progressive behavioral phenotype, consisting of slowed and irregular voluntary movements, gait ataxia, tremor and jerky movements, incoordination, and weight loss, with a shortened lifespan. Neuropathology included prominent intranuclear inclusions in cortex and striatum as well as cytoplasmic aggregates. This phenotype is very similar to the phenotypes of previous transgenic mice expressing N-terminal fragments of mutant Htt. The current HD-transgenic mice had nuclear accumulation of Htt, particularly an approximately 60-kDa fragment, which appears to represent an N-terminal cleavage product. This fragment is smaller than calpain or caspase-derived cleavage products of Htt, but it is comparable to a product, termed cp-A, which accumulates in nuclei of cells in a previously described cell model. This new mouse model may be useful in the future for pathogenic and preclinical therapeutic studies related to HD. The data suggest that proteolytic processing could be a part of the pathogenesis of HD, potentially representing an attractive therapeutic target. |
| first_indexed | 2024-12-14T00:37:54Z |
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| id | doaj.art-0f583253bf4e44ac933ae12f542f61b9 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-14T00:37:54Z |
| publishDate | 2006-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-0f583253bf4e44ac933ae12f542f61b92022-12-21T23:24:31ZengElsevierNeurobiology of Disease1095-953X2006-02-01212381391Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtinYuji Tanaka0Shuichi Igarashi1Masayuki Nakamura2Juliette Gafni3Cameron Torcassi4Gabrielle Schilling5Danielle Crippen6Jonathan D. Wood7Akira Sawa8Nancy A. Jenkins9Neal G. Copeland10David R. Borchelt11Christopher A. Ross12Lisa M. Ellerby13Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USADivision of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USADivision of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USAThe Buck Institute for Age Research, Novato, CA 94945, USAThe Buck Institute for Age Research, Novato, CA 94945, USADepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAThe Buck Institute for Age Research, Novato, CA 94945, USADivision of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USADivision of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 2120, USAMouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USAMouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USADepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADivision of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 2120, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding authors. C.A. Ross is to be contacted at Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA. L.M. Ellerby, The Buck Institute for Age Research, Novato, CA 94945, USA.The Buck Institute for Age Research, Novato, CA 94945, USA; Corresponding authors. C.A. Ross is to be contacted at Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA. L.M. Ellerby, The Buck Institute for Age Research, Novato, CA 94945, USA.Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics, we have generated a new inducible mouse model of HD expressing full-length huntingtin (Htt) using a tetracycline-regulated promoter. In double transgenic mice Htt was expressed widely in the brain under the control of the tet-transactivator (tTA) driven by the prion promoter PrP (in the absence of doxycycline). Mice expressing full-length mutant Htt, but not full-length normal Htt, displayed a progressive behavioral phenotype, consisting of slowed and irregular voluntary movements, gait ataxia, tremor and jerky movements, incoordination, and weight loss, with a shortened lifespan. Neuropathology included prominent intranuclear inclusions in cortex and striatum as well as cytoplasmic aggregates. This phenotype is very similar to the phenotypes of previous transgenic mice expressing N-terminal fragments of mutant Htt. The current HD-transgenic mice had nuclear accumulation of Htt, particularly an approximately 60-kDa fragment, which appears to represent an N-terminal cleavage product. This fragment is smaller than calpain or caspase-derived cleavage products of Htt, but it is comparable to a product, termed cp-A, which accumulates in nuclei of cells in a previously described cell model. This new mouse model may be useful in the future for pathogenic and preclinical therapeutic studies related to HD. The data suggest that proteolytic processing could be a part of the pathogenesis of HD, potentially representing an attractive therapeutic target.http://www.sciencedirect.com/science/article/pii/S0969996105002160 |
| spellingShingle | Yuji Tanaka Shuichi Igarashi Masayuki Nakamura Juliette Gafni Cameron Torcassi Gabrielle Schilling Danielle Crippen Jonathan D. Wood Akira Sawa Nancy A. Jenkins Neal G. Copeland David R. Borchelt Christopher A. Ross Lisa M. Ellerby Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin Neurobiology of Disease |
| title | Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin |
| title_full | Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin |
| title_fullStr | Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin |
| title_full_unstemmed | Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin |
| title_short | Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin |
| title_sort | progressive phenotype and nuclear accumulation of an amino terminal cleavage fragment in a transgenic mouse model with inducible expression of full length mutant huntingtin |
| url | http://www.sciencedirect.com/science/article/pii/S0969996105002160 |
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