Acta Neuropathologica

, Volume 115, Issue 1, pp 71–86 | Cite as

CAG repeat disorder models and human neuropathology: similarities and differences

  • Mitsunori Yamada
  • Toshiya Sato
  • Shoji Tsuji
  • Hitoshi Takahashi


CAG repeat diseases are hereditary neurodegenerative disorders caused by expansion of a polyglutamine tract in each respective disease protein. They include at least nine disorders, including Huntington’s disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and the spinocerebellar ataxias SCA1, SCA2, SCA3 (also known as Machado-Joseph disease), SCA6, SCA7, and SCA17. It is thought that a gain of toxic function resulting from the protein mutation plays important and common roles in the pathogenesis of these diseases. Recent studies have disclosed that, in addition to the presence of clinical phenotypes and conventional neuropathology in each disease, human brains affected by CAG repeat diseases share several polyglutamine-related changes in their neuronal nuclei and cytoplasm including the formation of intranuclear inclusions. Although these novel pathologic changes also show a distribution pattern characteristic to each disease, they are generally present beyond the lesion distribution of neuronal loss, suggesting that neurons are affected much more widely than has been recognized previously. Various mouse models of CAG repeat diseases have revealed that CAG repeat lengths, which are responsible for polyglutamine diseases in humans, are not sufficient for creating the conditions characteristic of each disease in mice. Although high expression of mutant proteins in mice results in the successful generation of polyglutamine-related changes in the brain, there are still some differences from human pathology in the lesion distribution or cell types that are affected. In addition, no model has yet successfully reproduced the specific neuronal loss observed in humans. Although there are no models that fully represent the neuropathologic changes present in humans, the data obtained have provided evidence that clinical onset is not clearly associated with neuronal cell death, but depends on intranuclear accumulation of mutant proteins in neurons.


CAG repeat disease Polyglutamine Animal model Pathology 



We thank S. Egawa, Y. Ohta, C. Tanada, J. Takasaki, N. Kaneko, T. Tanabe and Y. Itou for their technical assistance, and M. Machida and Y. Ueda for their secretarial assistance. This research was supported by a grant from the Research Committee for Ataxic Diseases, the Ministry of Health, Labor and Welfare, Japan, a Grant-in-Aid for Scientific Research (17300109), and a Grant-in-Aid for Scientific Research on Priority Areas-Advanced Brain Project (15016044) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Mitsunori Yamada
    • 1
  • Toshiya Sato
    • 2
  • Shoji Tsuji
    • 3
  • Hitoshi Takahashi
    • 1
  1. 1.Department of Pathology, Brain Research InstituteNiigata UniversityNiigataJapan
  2. 2.Department of Comparative and Experimental Medicine, Brain Research InstituteNiigata UniversityNiigataJapan
  3. 3.Department of Neurology, Graduate School of MedicineUniversity of TokyoTokyoJapan

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