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Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome

Hui Zhou1, Fengli Cao, Zhishan Wang

  • 1Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322, USA.

The Journal of Cell Biology
|October 15, 2003
PubMed
Summary
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Toxic huntingtin (htt) fragments in Huntington's disease (HD) are generated and accumulate due to decreased proteasome activity. Restoring fragment removal may be a more effective HD therapy than inhibiting production.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin (HTT) gene.
  • NH2-terminal mutant huntingtin (htt) fragments are implicated in HD pathogenesis, but their generation and toxic mechanisms remain unclear.

Purpose of the Study:

  • To investigate the generation and accumulation of NH2-terminal mutant htt fragments in HD.
  • To explore the role of proteasome activity in the toxicity of these fragments.

Main Methods:

  • Utilized htt-transfected cells and HD knockin mouse models.
  • Analyzed neuronal nuclear inclusions and proteasome activity.
  • Investigated the effect of proteasome inhibition on htt fragment aggregation.

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Main Results:

  • Generated complex NH2-terminal mutant htt fragments (<508 amino acids) in cells and mouse brains.
  • These fragments formed neuronal nuclear inclusions preceding neurological symptoms.
  • Fragment accumulation correlated with age-dependent proteasome decline and was exacerbated by proteasome inhibition.

Conclusions:

  • Decreased proteasome activity contributes to late-onset htt toxicity in HD.
  • Therapeutic strategies aimed at enhancing the clearance of NH2-terminal htt fragments may be more effective than inhibiting their production.