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Hippi! Understanding Huntington's Disease

  January, 28 2002 4:05
your information resource in human molecular genetics
Huntington’s disease (HD) is a degenerative disease that affects neurons in the body and in the brain, and leads to the early decline of physical and intellectual capacities. The disease affects 250, 000 people in the United States and approximately 6,000 people in the United Kingdom, and there is no effective cure or treatment available at present.

Loss of neurons in the brain of patients with HD is due to neural cell death. But what activates the cell death pathway in diseased brains? Don Nicholson and colleagues now propose an attractive model in the February issue of Nature Cell Biology (Vol. 4, No. 2) that could pave the way for new strategies to interfere with neurodegeneration.

HD is caused by mutations of the huntingtin gene, which lead to the expression of a mutant Huntingtin protein (Htt). In the normal brain, the Hip-1 protein interacts with Htt. But Nicholson and colleagues now show that the affinity of Hip-1 for mutant Htt is much lower than its affinity for wild-type Htt. They also identify another partner for Hip-1, Hippi, and show that the interaction between Hip-1 and Htt on the one hand, and between Hip-1 and Hippi on the other, are mutually exclusive. So, in diseased brains, levels of the Hip-1/Hippi complex are increased relative to levels of the Hip-1/Htt complex. The authors go on to show that the proenzyme procaspase-8, one of the effectors of apoptosis, is recruited to Hip-1/Hippi complexes and activated, presumably as a result of its dimerization by Hip-1 and Hippi, thus initiating the apoptotic cascade.
Interfering with this pathway would thus be expected to reduce neural loss in HD brains, but only further experimentation will tell whether such strategies fulfil their promise.

Author contact:

Dr Donald Nicholson
Merck Frosst Centre for Therapeutic Research
Pointe-Claire-Dorval, Quebec
Tel: +1 514 428 8544
E--mail: donald_nicholson@merck.com

For an advanced online publication of this paper go to AOP

(C) Nature Cell Biology press release.

Message posted by: Trevor M. D'Souza

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