What causes the damage in Huntington's Disease?

It's humbling that we now have so many disease genes cloned but still so little knowledge of how to use that genetic information to cure or understand many of these diseases. The gene for Huntington's Disease was cloned many years ago. But the gene sequence information has not lead to a cure. At last there is some inkling of how the gene may actually relate to the disease. A very nice paper by Ricki Lewis in The Scientist (1) summarizes some recent developments. My discussion below is largely derived from that paper.

Huntington’s disease (HD) was described over 100 years ago by Dr. George Huntington, an American physician who worked in Long Island New York (2). The dominant genetic pattern was also recognized at that time. Though a lot of excellent genetic pedigree analysis was done over the next 100 years, the “breakthrough” paper which will probably still be quoted in the next millenium was written by James Gusella and collaborators (3). They localized the gene defect to a genetic marker called G8 and found a gene called IT15 (“interesting transcript 15”) that was located within the G8 region. The gene product, a protein, was labelled “huntingtin.” In normal individuals huntingtin has a stretch of 34 glutamines. In people with HD this sequence of amino acids is elongated, it spans at least 40 glutamines (4). An increase in a sequence of glutamines is actually a commonly observed pattern in genetic disease, particularly neurological genetic disease. But how does having too many glutamines in the huntingtin protein lead to HD?

This question has vexed many neuroscientists years. An initial explanation was that the elongated stretch of glutamines produced excitotoxicity. Glutamic acid is an excitatory amino acid. It is vital in neurotransmission. But too much glutamic acid can overstimulate neurons and injure them. So possibly too many glutamines in a protein can make the protein neurotoxic. This is good idea, and it still may be significant, but no one has yet shown that the huntingtin protein actually interacts significantly with glutamate receptors.
More recent research appears to have found some possible mechanisms whereby the huntingtin mutation could cause significant neurological damage.

Mutant huntingtin may inhibit transcription in two possible ways.

1. In the normal process of transcription an important transcription factor is the cyclic AMP response element binding protein (CREB). The cyclic AMP response element is often abbreviated as CRE. There is another factor called CBP, the CREB binding protein, which apparently helps CREB performs its functions.

Huntingtin may interfere with CBP in two ways. CBP possess a stretch of 18 glutamines. According to Nucifora et al. it appears that the glutamines in the abnormally elongated huntingtin protein can bind the sequence of glutamines in CBP, inhibit CBP activity and thus inhibit transcription (5). In addition, CBP possess a site of enzyme activity. The activity is a type of “acetyltransferase” activity. It transfers an acetyl group (i.e. acetylates) some histone proteins. Proper acetylation of histones helps turn on transcription. A paper by Steffan et al. shows that mutant huntingtin can block the acetyltransferase activity of CBP. Not only that, but certain drugs---histone deacetylase inhibitors---can block the damage caused by the huntingtin (at least in a model system used the fly, Drosophila melanogaster) (6).
2. Disruption of protein degradation
Cells have certain ways of getting rid of damaged proteins. One way is by binding ubiquitin (a rather ubiquitous protein) to the damage protein. The ubiquinated proteins then go into a proteasome where they are processed and eliminated. Recent work by Bence, Sampat, and Kopito at Stanford suggests that the long tracts of glutamines in mutant huntingtin can gum up (so to speak) the proteasome system (7).

Suggestions for further reading. The first reference below, the review by Lewis, is probably the best source for anyone who wants to get a better understanding of the scientific research noted above. You can get her review on the internet at http://www.the-scientist.com/yr2003/may/hot_030519.html. You do have to register for The Scientist (which is free).
References:
1. Lewis, R. Huntington disease pathology unfolds. The Scientist. 17:32-33, 2003.
2. Huntington, G. W. On chorea. Medical Surgical Reporter. 26:317-21, 1872.
3. Gusella, J.F. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 306, 306: 234-8, 1983.
4. The Huntingtn’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is unstable in Huntington’s disease chromosomes. Cell, 72:971-83, 1993.
5. Nucifora, F. et al., Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science. 291:2423-8 2001.
6. Steffan J., et al., Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 413:739-43, 2001.
7. Bence N., et al., Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 292:1552-5, 2001.