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Apoptosis in Huntington's disease

Miriam A Hickey1, Marie Françoise Chesselet

  • 1Department of Neurology, Reed Neurological Research Center, B114, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, 90095, Los Angeles, CA, USA.

Progress in Neuro-Psychopharmacology & Biological Psychiatry
|March 27, 2003
PubMed

Insights

Huntington's disease (HD) involves neuronal loss due to a mutant huntingtin gene. While apoptosis is implicated, the exact cell death mechanisms, particularly the role of proapoptotic proteins, are still being investigated for HD pathogenesis.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Huntington's disease (HD) is a fatal autosomal dominant disorder characterized by progressive motor, psychiatric, and cognitive decline.
  • The primary pathology involves selective degeneration of striatal medium spiny GABAergic neurons, with up to 95% loss in late stages.
  • The disease is caused by an expanded polyglutamine tract in the huntingtin gene, but the precise mechanism of selective neuronal death remains unclear.

Purpose of the Study:

  • To review the evidence supporting the role of apoptotic pathways and processes in the pathogenesis of Huntington's disease.
  • To explore how mutant huntingtin and proapoptotic proteins contribute to selective neuronal cell death in HD.
  • To discuss the potential significance of apoptosis-related processes over apoptosis itself in HD.

Main Methods:

  • Review of existing scientific literature and in vitro studies.
  • Analysis of evidence linking apoptotic pathways to mutant huntingtin.
  • Examination of theories on proapoptotic protein upregulation and huntingtin cleavage.

Main Results:

  • While direct evidence of apoptosis in HD is scarce, in vitro studies suggest a connection between mutant huntingtin and apoptotic pathways.
  • Upregulation of proapoptotic proteins may lead to huntingtin cleavage, generating toxic fragments that disrupt transcription.
  • Increased proapoptotic proteins might contribute to the slow, selective neuronal death observed in HD.

Conclusions:

  • Apoptosis-related processes, rather than apoptosis per se, are likely key contributors to Huntington's disease pathogenesis.
  • The interplay between mutant huntingtin, proapoptotic proteins, and transcriptional disruption offers a plausible mechanism for selective neurodegeneration in HD.
  • Further research into these apoptotic mechanisms is crucial for understanding and potentially treating Huntington's disease.

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