A New Strategy For Fighting HD? - from Horizon #100, Spring 2001

Using the new YAC (yeast artificial chromosome) transgenic mouse developed in Dr. Michael Hayden’s laboratory, investigators at the University of British Columbia have discovered that the normal version of the huntingtin protein (called the “wild-type” protein) can protect cells from the toxic effect of mutant huntington.

Dr. Blair Leavitt and his colleagues have been working with YAC72 mice which express both mutant human huntingtin protein and varying levels of the endogenous, or wild-type, protein. Huntingtin protein is expressed at the highest levels in brain tissue and the testes.

Mice expressing mutant huntingtin but not any wild-type huntingtin experience massive cell death in the testes, are infertile, do not produce sperm, and have testicular atrophy.

However, says Dr. Leavitt, when increased amounts of wild-type protein are present, “the mice breed normally and have no evidence of increased testicular cell death”. In the YAC46 mouse (which has a smaller number of polyglutamines than the YAC72 model), there is less cell death in general, and increasing the levels of wild-type protein seems to have an even more dramatic effect in preventing cell death. YAC mice which express huntingtin with 18 polyglutamine repeats do not have any cell death, even in the absence of wild-type huntingtin.

These findings are of tremendous interest. First, they demonstrate the link between polyglutamine repeat length and cell death. Second and more importantly, says Dr. Leavitt, “they provide the first direct evidence that normal huntingtin protein may have therapeutic potential for reducing cell death in HD.” — RM/BL

See B. Leavitt, J. Guttman, G. Hodgson, G. Kimel, R. Singaraja, W. Vogl and M. Hayden (2001). Wild-type huntingtin reduces cellular toxicity of mutant huntington in vivo. Am J Hum Genet 68:313-324.