Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity.
Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
Hansson
O
O
Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Sölvegatan 17, S-223 62 Lund, Sweden. oskar.hansson@mphy.lu.se
Petersén
A
A
Leist
M
M
Nicotera
P
P
Castilho
R F
RF
Brundin
P
P
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002452:Cell Count; D002470:Cell Survival; D003342:Corpus Striatum / Q000187:drug effects*; D005091:Exons; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis; D009498:Neurotoxins / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists
D015415:Biomarkers; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D017378:Quinolinic Acid