Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice

Hirohide Sawada, Hiroshi Ishiguro, Kazuhiro Nishii, Koji Yamada, Kunihiro Tsuchida, Hisahide Takahashi, Jun Goto, Ichiro Kanazawa, Toshiharu Nagatsu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)559-573
Number of pages15
JournalNeuroscience Research
Volume57
Issue number4
DOIs
Publication statusPublished - 01-04-2007

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Neurons
Corpus Striatum
Neuropil
Huntington Disease
Nucleus Accumbens
Cell Death
Mutation
Proteins
polyglutamine
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Sawada, Hirohide ; Ishiguro, Hiroshi ; Nishii, Kazuhiro ; Yamada, Koji ; Tsuchida, Kunihiro ; Takahashi, Hisahide ; Goto, Jun ; Kanazawa, Ichiro ; Nagatsu, Toshiharu. / Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice. In: Neuroscience Research. 2007 ; Vol. 57, No. 4. pp. 559-573.
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Sawada, H, Ishiguro, H, Nishii, K, Yamada, K, Tsuchida, K, Takahashi, H, Goto, J, Kanazawa, I & Nagatsu, T 2007, 'Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice', Neuroscience Research, vol. 57, no. 4, pp. 559-573. https://doi.org/10.1016/j.neures.2007.01.002

Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice. / Sawada, Hirohide; Ishiguro, Hiroshi; Nishii, Kazuhiro; Yamada, Koji; Tsuchida, Kunihiro; Takahashi, Hisahide; Goto, Jun; Kanazawa, Ichiro; Nagatsu, Toshiharu.

In: Neuroscience Research, Vol. 57, No. 4, 01.04.2007, p. 559-573.

Research output: Contribution to journalArticle

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AU - Sawada, Hirohide

AU - Ishiguro, Hiroshi

AU - Nishii, Kazuhiro

AU - Yamada, Koji

AU - Tsuchida, Kunihiro

AU - Takahashi, Hisahide

AU - Goto, Jun

AU - Kanazawa, Ichiro

AU - Nagatsu, Toshiharu

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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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