Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells

Hum Mol Genet. 2000 Nov 22;9(19):2799-809. doi: 10.1093/hmg/9.19.2799.

Abstract

Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that are candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and Hdh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology*
  • Cytoplasm / metabolism
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Genes, Dominant*
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / pathology
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Iron / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation / genetics*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Oxygen / metabolism
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • Stem Cells / metabolism
  • Transferrin / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Receptors, Transferrin
  • Transferrin
  • Tumor Suppressor Protein p53
  • Iron
  • Oxygen