TY - JOUR
T1 - Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin
AU - Tanaka, Yuji
AU - Igarashi, Shuichi
AU - Nakamura, Masayuki
AU - Gafni, Juliette
AU - Torcassi, Cameron
AU - Schilling, Gabrielle
AU - Crippen, Danielle
AU - Wood, Jonathan D.
AU - Sawa, Akira
AU - Jenkins, Nancy A.
AU - Copeland, Neal G.
AU - Borchelt, David R.
AU - Ross, Christopher A.
AU - Ellerby, Lisa M.
N1 - Funding Information:
This work was supported by the National Institutes of Health grants NS16375, NS34172, and NS38144 (CAR) and NS40251A (LME). We are grateful to the Hereditary Disease Foundation and the High Q Foundation for their support to CAR and LME, and to the Huntington's Disease Society of America for their support to CAR (Coalition for the Cure), DRB, and LME. JG is supported by a National Institutes of Health postdoctoral fellowship F32 NS043937.
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.nbd.2005.07.014
DO - 10.1016/j.nbd.2005.07.014
M3 - Article
C2 - 16150600
AN - SCOPUS:30744439549
SN - 0969-9961
VL - 21
SP - 381
EP - 391
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -