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Related Experiment Videos

Polyglutamine pathogenesis.

C A Ross1, J D Wood, G Schilling

  • 1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. caross@jhu.edu

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
|August 6, 1999
PubMed
Summary
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Expanding CAG repeats cause neurodegenerative disorders like Huntington's disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA). Protein aggregation, nuclear localization, and processing are key to pathogenesis in these polyglutamine diseases.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Neurodegenerative disorders are increasingly linked to expanded CAG triplet repeats encoding polyglutamine.
  • Huntington's disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA) are polyglutamine diseases caused by mutations in different genes, serving as valuable models.

Purpose of the Study:

  • To review the roles of protein aggregation, nuclear localization, and proteolytic processing in the pathogenesis of polyglutamine neurodegenerative diseases.
  • To present findings from cell and mouse models of HD and DRPLA.

Main Methods:

  • Cell model studies examining huntingtin fragments with expanded repeats.
  • Construction and analysis of mouse models for HD (N171 huntingtin) and DRPLA (full-length atrophin-1).

Related Experiment Videos

  • Investigating the impact of nuclear import/export signals on huntingtin toxicity.

    • Main Results:

    • Truncated huntingtin with expanded repeats forms more aggregates, localizes more to the nucleus, and causes greater toxicity than full-length huntingtin.
    • HD and DRPLA mouse models exhibit neuronal nuclear abnormalities (diffuse staining, inclusion bodies), implicating the nucleus in dysfunction.
    • Proteolytic processing of atrophin-1 fragments appears critical for DRPLA pathogenesis.

    Conclusions:

    • The nucleus is a primary site of neuronal dysfunction in polyglutamine diseases.
    • Proteolytic processing, nuclear localization, and protein aggregation collectively contribute to the pathogenesis of HD and DRPLA.