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Pathological mechanisms in Huntington's disease and other polyglutamine expansion diseases

A Lunkes1, Y Trottier, J L Mandel

  • 1Institut de Génétique et Biologie Moléculaire et Cellulaire, INSERM/CNRS/Université Louis Pasteur, Illkirch, France.

Essays in Biochemistry
|September 17, 1999
PubMed

Insights

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. This expansion leads to toxic protein aggregation and neuronal death, but the exact mechanism remains unclear.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder.
  • It is characterized by involuntary movements, cognitive decline, and mood disturbances.
  • Pathologically, HD involves significant neuronal loss in the striatum and cerebral cortex.

Purpose of the Study:

  • To investigate the genetic basis of Huntington's disease.
  • To understand the molecular mechanisms underlying polyglutamine expansion diseases.
  • To explore the formation and role of intracellular inclusions in neurodegeneration.

Main Methods:

  • Analysis of brain tissue from HD patients and mouse models.
  • Molecular and cellular studies focusing on protein aggregation.
  • Genetic analysis of CAG repeat expansions in the huntingtin gene.

Main Results:

  • The genetic defect in HD is an expanded CAG repeat in the huntingtin gene, encoding a polyglutamine stretch.
  • The size of the CAG expansion correlates inversely with the age of HD onset.
  • Abnormal intracellular inclusions, formed by aggregated mutant huntingtin protein, are observed in affected brains.

Conclusions:

  • Polyglutamine expansion is a novel mechanism of neurodegeneration, implicated in HD and seven other inherited disorders.
  • Mutant huntingtin protein gains a toxic function due to polyglutamine expansion.
  • The precise mechanisms by which polyglutamine expansion causes selective neuronal dysfunction and death are still under investigation.

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