Pathogenic mechanisms in Huntington's disease

Int Rev Neurobiol. 2011;98:373-418. doi: 10.1016/B978-0-12-381328-2.00015-8.

Abstract

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder presenting in midlife. Multiple pathogenic mechanisms which hypothesise how the expanded CAG repeat causes manifest disease have been suggested since the mutation was first detected. These mechanisms include events that operate at both the gene and protein levels. It has been proposed that somatic instability of the CAG repeat could underlie the striatal-specific pathology observed in HD, although how this occurs and what consequences this has in the disease state remain unknown. The form in which the Htt protein exists within the cell has been extensively studied in terms of both its role in aggregate formation and its cellular processing. Protein-protein interactions, post-translational modifications and protein cleavage have all been suggested to contribute to HD pathogenesis. The potential downstream effects of the mutant Htt protein are also noted here. In particular, the adverse effect of the mutant Htt protein on cellular protein degradation, subcellular transport and transcription are explored, and its role in energy metabolism and excitotoxicity investigated. Elucidating the mechanisms at work in HD pathogenesis and determining when they occur in relation to disease is an important step in the pathway to therapeutic interventions.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / pathology*
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Protein Processing, Post-Translational / genetics
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins