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01-01-2008 | Review

CAG repeat disorder models and human neuropathology: similarities and differences

Authors: Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Hitoshi Takahashi

Published in: Acta Neuropathologica | Issue 1/2008

Abstract

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.

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Title: CAG repeat disorder models and human neuropathology: similarities and differences
Authors: Mitsunori Yamada
Toshiya Sato
Shoji Tsuji
Hitoshi Takahashi
Publication date: 01-01-2008
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 1/2008
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-007-0287-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

CAG repeat disorder models and human neuropathology: similarities and differences

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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