Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease.
Huntington disease (HD), caused by expansion >35 of a polyglutamine tract in huntingtin, results in degeneration of striatal medium spiny neurons (MSNs). Previous studies demonstrated mitochondrial dysfunction, altered intracellular calcium release, and enhanced NMDAR-mediated current and apoptosis in cellular and mouse models of HD. Here, we exposed cultured MSNs from YAC transgenic mice, expressing full-length human huntingtin with 18, 72, or 128 repeats, to a variety of apoptosis-inducing compounds that inhibit mitochondrial function or increase intracellular calcium, and assessed apoptosis 24 h later. All compounds produced a polyglutamine length-dependent increase in apoptosis, but NMDA produced the largest potentiation in apoptosis of YAC72 and YAC128 versus YAC18 MSNs. Moreover, reduction of NMDAR-mediated current and calcium influx in YAC72 MSNs to levels seen in wild-type reduced NMDAR-mediated apoptosis proportionately to wild-type levels. Our results suggest that increased NMDAR signaling plays a major role in enhanced excitotoxic MSN death in this HD mouse model.
Shehadeh
Jacqueline
J
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Fernandes
Herman B
HB
Zeron Mullins
Melinda M
MM
Graham
Rona K
RK
Leavitt
Blair R
BR
Hayden
Michael R
MR
Raymond
Lynn A
LA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium