Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines.


Journal Article

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding huntingtin protein (Htt), but the mechanisms by which this mutant protein causes neurodegeneration remain unknown. Here we show that lymphoblast mitochondria from patients with HD have a lower membrane potential and depolarize at lower calcium loads than do mitochondria from controls. We found a similar defect in brain mitochondria from transgenic mice expressing full-length mutant huntingtin, and this defect preceded the onset of pathological or behavioral abnormalities by months. By electron microscopy, we identified N-terminal mutant huntingtin on neuronal mitochondrial membranes, and by incubating normal mitochondria with a fusion protein containing an abnormally long polyglutamine repeat, we reproduced the mitochondrial calcium defect seen in human patients and transgenic animals. Thus, mitochondrial calcium abnormalities occur early in HD pathogenesis and may be a direct effect of mutant huntingtin on the organelle.

Full Text

Duke Authors

Cited Authors

  • Panov, AV; Gutekunst, C-A; Leavitt, BR; Hayden, MR; Burke, JR; Strittmatter, WJ; Greenamyre, JT

Published Date

  • August 2002

Published In

Volume / Issue

  • 5 / 8

Start / End Page

  • 731 - 736

PubMed ID

  • 12089530

Pubmed Central ID

  • 12089530

International Standard Serial Number (ISSN)

  • 1097-6256

Digital Object Identifier (DOI)

  • 10.1038/nn884


  • eng

Conference Location

  • United States