TY - JOUR
T1 - Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice
AU - Sawada, Hirohide
AU - Ishiguro, Hiroshi
AU - Nishii, Kazuhiro
AU - Yamada, Kouji
AU - Tsuchida, Kunihiro
AU - Takahashi, Hisahide
AU - Goto, Jun
AU - Kanazawa, Ichiro
AU - Nagatsu, Toshiharu
N1 - Funding Information:
We thank Dr. S. Murayama (Tokyo Metropolitan Institute of Gerontology) and Dr. Y. Ohya (Musashi Hospital, National Center of Neurology and Psychiatry) for their advice on neuropathology and histological techniques, Dr. N. Yoshimura (Aomori University of Health and Welfare) for helpful discussion about neuropathology. We also thank Dr. M. Sawada (Nagoya University, Research Institute of Environmental Medicine) for his support of this work. This study was supported by Grants-in-Aid for Scientific Research on Priority Areas and on Comprehensive Promotion of Study of Brain from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and from the Ministry of Health, Labor and Welfare of Japan.
PY - 2007/4
Y1 - 2007/4
N2 - Huntington's disease (HD) is caused by a mutation causing expanded polyglutamine tracts in the N-terminal fragment of huntingtin. A pathological hallmark of HD is the formation of aggregates in the striatal neurons. Here we report that ageing human huntingtin knock-in mice expressing mutant human huntingtin contained neuronal huntingtin aggregates, as revealed by immunohistochemical analysis. In heterozygous knock-in mice with 77 CAG repeats, aggregates of N-terminal fragments of huntingtin were specifically formed in nuclei and neuropils in the striatal projection neurons, and in neuropils in their projection regions. This aggregate formation progressed depending on age, became interacted with proteolytic or chaperone proteins, and occurred most prominently in the nucleus accumbens. These mutant mice demonstrated abnormal aggressive behavior. In homozygous knock-in mice, heavy deposits of intranuclear and neuropil aggregates were detected, which extended to other regions; and characteristic large perikaryal aggregates were also found in the affected neurons. However, cell death was not observed among the striatal and affected neurons of these mutant mice. Our results indicate that the polyglutamine aggregates do not necessarily correlate with neuronal death. These human huntingtin knock-in mice should be useful to provide an effective therapeutic approach against HD.
AB - Huntington's disease (HD) is caused by a mutation causing expanded polyglutamine tracts in the N-terminal fragment of huntingtin. A pathological hallmark of HD is the formation of aggregates in the striatal neurons. Here we report that ageing human huntingtin knock-in mice expressing mutant human huntingtin contained neuronal huntingtin aggregates, as revealed by immunohistochemical analysis. In heterozygous knock-in mice with 77 CAG repeats, aggregates of N-terminal fragments of huntingtin were specifically formed in nuclei and neuropils in the striatal projection neurons, and in neuropils in their projection regions. This aggregate formation progressed depending on age, became interacted with proteolytic or chaperone proteins, and occurred most prominently in the nucleus accumbens. These mutant mice demonstrated abnormal aggressive behavior. In homozygous knock-in mice, heavy deposits of intranuclear and neuropil aggregates were detected, which extended to other regions; and characteristic large perikaryal aggregates were also found in the affected neurons. However, cell death was not observed among the striatal and affected neurons of these mutant mice. Our results indicate that the polyglutamine aggregates do not necessarily correlate with neuronal death. These human huntingtin knock-in mice should be useful to provide an effective therapeutic approach against HD.
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U2 - 10.1016/j.neures.2007.01.002
DO - 10.1016/j.neures.2007.01.002
M3 - Article
C2 - 17335925
AN - SCOPUS:33947158092
SN - 0168-0102
VL - 57
SP - 559
EP - 573
JO - Neuroscience Research
JF - Neuroscience Research
IS - 4
ER -