Wild-type huntingtin protects neurons from excitotoxicity
Article first published online: 17 JAN 2006
Journal of Neurochemistry
Volume 96, Issue 4, pages 1121–1129, February 2006
How to Cite
Leavitt, B. R., van Raamsdonk, J. M., Shehadeh, J., Fernandes, H., Murphy, Z., Graham, R. K., Wellington, C. L., Lynn A. Raymond and Hayden, M. R. (2006), Wild-type huntingtin protects neurons from excitotoxicity. Journal of Neurochemistry, 96: 1121–1129. doi: 10.1111/j.1471-4159.2005.03605.x
- Issue published online: 26 JAN 2006
- Article first published online: 17 JAN 2006
- Received August 5, 2005; revised manuscript received October 13, 2005; accepted October 18, 2005.
- Huntington's disease;
Huntingtin is a caspase substrate, and loss of normal huntingtin function resulting from caspase-mediated proteolysis may play a role in the pathogenesis of Huntington disease. Here we tested the hypothesis that increasing huntingtin levels protect striatal neurons from NMDA receptor-mediated excitotoxicity. Cultured striatal neurons from yeast artificial chromosome (YAC)18 transgenic mice over-expressing full-length wild-type huntingtin were dramatically protected from apoptosis and caspase-3 activation compared with cultured striatal neurons from non-transgenic FVB/N littermates and YAC72 mice expressing mutant human huntingtin. NMDA receptor activation induced by intrastriatal injection of quinolinic acid initiated a form of apoptotic neurodegeneration within the striatum of mice that was associated with caspase-3 cleavage of huntingtin in neurons and astrocytes, decreased levels of full-length huntingtin, and the generation of a specific N-terminal caspase cleavage product of huntingtin. In vivo, over-expression of wild-type huntingtin in YAC18 transgenic mice conferred significant protection against NMDA receptor-mediated apoptotic neurodegeneration. These data provide in vitro and in vivo evidence that huntingtin may regulate the balance between neuronal survival and death following acute excitotoxic stress, and that the levels of huntingtin may modulate neuronal sensitivity to excitotoxic neurodegeneration. We suggest that further study of huntingtin's anti-apoptotic function will contribute to our understanding of the pathogenesis of Huntingdon's disease and provide insights into the selective vulnerability of striatal neurons to excitotoxic cell death.