Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice.
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.
Sawada
Hirohide
H
Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan. hsawada@fujita-hu.ac.jp
Ishiguro
Hiroshi
H
Nishii
Kazuhiro
K
Yamada
Kouji
K
Tsuchida
Kunihiro
K
Takahashi
Hisahide
H
Goto
Jun
J
Kanazawa
Ichiro
I
Nagatsu
Toshiharu
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000166:cytology; D006801:Humans; D000071058:Huntingtin Protein; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019581:Neuropil / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000502:physiology; D013997:Time Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins