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March 28, 2014
A Huntington's Breakthrough?
Huntington's is a terrible disease. It's the perfect example of how genomics can only take you so far. We've known since 1993 what the gene is that's mutated in the disease, and we know the protein that it codes for (Huntingtin). We even know what seems to be wrong with the protein - it has a repeating chain of glutamines on one end. If your tail of glutamines is less than about 35 repeats, then you're not going to get the disease. If you have 36 to 39 repeats, you are in trouble, and may very well come down with the less severe end of Huntington's. If there are 40 or more, doubt is tragically removed.
So we can tell, with great precision, if someone is going to come down with Huntington's, but we can't do a damn thing about it. That's because despite a great deal of work, we don't really understand the molecular mechanism at work. This mutated gene codes for this defective protein, but we don't know what it is about that protein that causes particular regions of the brain to deteriorate. No one knows what all of Huntingtin's functions are, and not for lack of trying, and multiple attempts to map out its interactions (and determine how they're altered by a too-long N-terminal glutamine tail) have not given a definite answer.
But maybe, as of this week, that's changed. Solomon Snyder's group at Johns Hopkins has a paper out in Nature that suggests an actual mechanism. They believe that mutant Huntingtin binds (inappropriately) a transcription factor called "specificity protein 1", which is known to be a major player in neurons. Among other things, it's responsible for initiating transcription of the gene for an enzyme called cystathionine γ-lyase. That, in turn, is responsible for the last step in cysteine biosynthesis, and put together, all this suggests a brain-specific depletion of cysteine. Update: this could have numerous downstream consequences - this is the pathway that produces hydrogen sulfide, which the Snyder group has shown is an important neurotransmitter (one of several they've discovered), and it's also involved in synthesizing glutathione. Cysteine itself is, of course, often a crucial amino acid in many protein structures as well.)
Snyder is proposing this as the actual mechanism of Huntington's, and they have shown, in human tissue culture and in mouse models of the disease, that supplementation with extra cysteine can stop or reverse the cellular signs of the disease. This is a very plausible theory (it seems to me), and the paper makes a very strong case for it. It should lead to immediate consequences in the clinic, and in the labs researching possible therapies for the disease. And one hopes that it will lead to immediate consequences for Huntington's patients themselves. If I knew someone with the Huntingtin mutation, I believe that I would tell them to waste no time taking cysteine supplements, in the hopes that some of it will reach the brain.
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