Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults.
Glutamate-mediated excitotoxicity might contribute to the pathogenesis of Huntington's disease and other polyglutamine repeat disorders. We used murine neocortical cultures derived from transgenic and knock-in mice to test the effect of expression of expanded polyglutamine-containing huntingtin on neuronal vulnerability to excitotoxins or other insults. Neurons cultured from mice expressing either a normal length (Hdh(Q20)) or expanded (Hdh(Q111)) CAG repeat as a knock-in genetic alteration in exon one of the mouse Hdh gene [Hum Mol Genet 8 (1999) 115] had similar vulnerability to N-methyl-D-aspartate (NMDA) and kainate-mediated excitotoxicity. These neurons also exhibited similar vulnerability to oxidative stress (24 h exposure to 10-100 microM paraquat or 1-10 microM menadione), apoptosis (48 h exposure to 30-100 nM staurosporine or 1 microM dizocilpine maleate (MK-801) and proteasome inhibition (48 h exposure to 0.3-3 microM MG-132). Neocortical neurons cultured from mice transgenic for an expanded CAG repeat-containing exon 1 of the human HD gene (Mangiarini et al., 1996, R6/2 line) and non-transgenic littermate controls also had similar vulnerability to NMDA and kainate-mediated excitotoxicity. These observations suggest that expression of expanded polyglutamine-containing huntingtin does not acutely alter the vulnerability of cortical neurons to excitotoxic, oxidative or apoptotic insults.
Snider
B J
BJ
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid, St. Louis, MO 63110, USA. sniderj@neuro.wustl.edu
Moss
J L
JL
Revilla
F J
FJ
Lee
C-S
CS
Wheeler
V C
VC
Macdonald
M E
ME
Choi
D W
DW
D000818:Animals; D017209:Apoptosis; D018929:Cell Culture Techniques; D015870:Gene Expression; D005838:Genotype; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress; D010455:Peptides / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D016202:N-Methylaspartate; D007608:Kainic Acid