Mutant huntingtin enhances excitotoxic cell death

Mol Cell Neurosci. 2001 Jan;17(1):41-53. doi: 10.1006/mcne.2000.0909.

Abstract

Evidence suggests overactivation of NMDA-type glutamate receptors (NMDARs) contributes to selective degeneration of medium-sized spiny striatal neurons in Huntington's disease (HD). Here we determined whether expression of huntingtin containing the polyglutamine expansion augments NMDAR-mediated excitotoxicity. HEK293 cells coexpressing mutant huntingtin (htt-138Q) and either NR1A/NR2A- or NR1A/NR2B-type NMDARs exposed to 1 mM NMDA showed a significant increase in excitotoxic cell death compared to controls (cells coexpressing htt-15Q or GFP), but the difference was larger for NR1A/NR2B. Moreover, agonist-dependent cell death showed apoptotic features for cells coexpressing htt-138Q and NR1A/NR2B, but not for cells expressing htt-138Q and NR1A/NR2A. Further, NR1A/NR2B-mediated apoptosis was not seen with coexpression of an N-terminal fragment of mutant htt. Since NR1A/NR2B is the predominant NMDAR subtype in neostriatal medium-sized spiny neurons, enhancement of NMDA-induced apoptotic death in NR1A/NR2B-expressing cells by full-length mutant htt may contribute to selective neurodegeneration in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Cell Death / drug effects*
  • Cell Death / genetics
  • Cell Line
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / toxicity
  • Genes, Reporter
  • Green Fluorescent Proteins
  • Humans
  • Huntingtin Protein
  • Huntington Disease / etiology*
  • Huntington Disease / genetics
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Luminescent Proteins / genetics
  • Mutation*
  • N-Methylaspartate / toxicity
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / toxicity*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / toxicity*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Transfection
  • beta-Galactosidase / genetics

Substances

  • Excitatory Amino Acid Agonists
  • HTT protein, human
  • Huntingtin Protein
  • Luminescent Proteins
  • NR1 NMDA receptor
  • NR2A NMDA receptor
  • NR2B NMDA receptor
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptide Fragments
  • Protein Isoforms
  • Receptors, N-Methyl-D-Aspartate
  • Green Fluorescent Proteins
  • N-Methylaspartate
  • beta-Galactosidase