Mutant huntingtin enhances excitotoxic cell death.
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.
Zeron
M M
MM
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Chen
N
N
Moshaver
A
A
Lee
A T
AT
Wellington
C L
CL
Hayden
M R
MR
Raymond
L A
LA
D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology* / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D009154:Mutation; D016202:N-Methylaspartate / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics
D018690:Excitatory Amino Acid Agonists; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D001616:beta-Galactosidase