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Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease.
- Source :
-
Molecular and cellular neurosciences [Mol Cell Neurosci] 2004 Mar; Vol. 25 (3), pp. 469-79. - Publication Year :
- 2004
-
Abstract
- Evidence suggests N-methyl-D-aspartate receptor (NMDAR) activation is involved in the degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). We tested the hypothesis that enhanced NMDAR-mediated excitotoxicity is mediated by the mitochondrial-associated apoptotic pathway in cultured MSNs from YAC transgenic mice expressing full-length huntingtin (htt) with a polyglutamine (polyQ) expansion of 46 or 72 (YAC46 or YAC72). NMDAR-mediated Ca(2+) transients and mitochondrial membrane depolarization were significantly increased in YAC compared to wild-type mice MSNs. Inhibitors of the mitochondrial permeability transition (mPT), cyclosporin A and bongkrekic acid, and coenzyme Q10 (an anti-oxidant involved in bioenergetic metabolism) dramatically diminished NMDA-induced cell death and eliminated genotypic differences. In YAC46 MSNs, NMDA stimulated significantly higher activation of caspase-3 and caspase-9 but not caspase-8, and NMDA-induced caspase-3 and -9 activation was markedly attenuated by cyclosporin A. Agents that improve mitochondrial function or inhibit the permeability transition may eliminate increased caspase activation and cell death associated with enhanced NMDAR activity in HD.
- Subjects :
- Animals
Cells, Cultured
Chromosomes, Artificial, Yeast genetics
Huntington Disease genetics
Mice
Mice, Transgenic
Neostriatum metabolism
Receptors, N-Methyl-D-Aspartate genetics
Apoptosis physiology
Chromosomes, Artificial, Yeast metabolism
Disease Models, Animal
Huntington Disease metabolism
Receptors, N-Methyl-D-Aspartate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1044-7431
- Volume :
- 25
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular and cellular neurosciences
- Publication Type :
- Academic Journal
- Accession number :
- 15033175
- Full Text :
- https://doi.org/10.1016/j.mcn.2003.11.014