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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 28, 2014

A Huntington's Breakthrough?

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Posted by Derek

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.

Comments (20) + TrackBacks (0) | Category: Biological News | The Central Nervous System


1. Paul Brookes on March 28, 2014 7:59 AM writes...

Nice write-up, but you missed the H2S angle. CSE is a major source of H2S in the brain and other tissues. Given the extensive literature on neurotransmission and other roles of H2S (it has a lot of overlap with NO signaling), it's not unreasonable to suggest the phenotype is actually due to lack of H2S.

A role for dysfunctional H2S signaling in neurological conditions is not especially new. There was some talk a few years ago about a role for sulfide in Down's syndrome - CBS is encoded on chromosome 21 so Down's patients have more of it. This is thought to underlie the "bulletproof" nature of individuals with the condition - they're very resistant to stress/trauma and sulfide is known to play a protective role in conditions such as ischemia.

Globally, given random distributions, there would be a predicted number of people with both conditions. The numbers are probably too small for a proper statistical analysis, but I would take a bet there's exclusivity between HD and Down's syndrome in the real world (i.e., nobody with both).

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2. Derek Lowe on March 28, 2014 8:41 AM writes...

Just added a bit more about that - thanks. No doubt that's where Snyder's group got into this story, since hydrogen sulfide is one of their pet neurotransmitters. But lack of Cys could do harm in several different directions, not just the neurotransmitter.

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3. Mike Parker on March 28, 2014 8:42 AM writes...

Isn't N-acetylcysteine supplementation (to boost cysteine levels) already used for various neurodegenerative disorders including Huntington's disease?

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4. supplement joe on March 28, 2014 9:23 AM writes...

Oral dosed N-acetyl etc is nasty and not very useful and cysteine won't get far either that way; now maybe cystine will but then this begs the question - what if cystine uptake is the problem all along? Say, you don't process the amino acid because of a co-factor problem. Now there is another trail into the woods….but nice work those boys did. Shows what might happen if you can get the horse to the corral.

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5. DSpeiser on March 28, 2014 9:45 AM writes...

Very exciting. As a postdoc many years ago we found a link between sulfide metabolism and purine synthesis, while pursuing heavy metal tolerance in S pombe which is mediated by glutathione and phytochelatins, which are esentially poly-glutathione. As a tragic note, my PI's wife was later diagnosed with Huntington's. SO I'm thrilled there is a way forward on this horrible disease.

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6. Anon on March 28, 2014 9:54 AM writes...

Interesting, though I'd like to hope in an ideal world we would give Bindu and Juan credit since it was their hands and likely their thinking [supporting by the PI's funding]. Especially as none of Solomon's grants in the RePORTER database come very close to this.
Maybe help them get some publicity and land a job one of these days.

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7. rudolphc on March 28, 2014 10:31 AM writes...

It might be interesting to examine the effects of NACA (ref. and citation therein)
on reverting CSE depletion since it is more BBB penetrable.

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8. Dave on March 28, 2014 10:43 AM writes...

Maybe this will fit in with some of the work being done on FTLD, and, especially Pick's Disease.


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9. Kelvin Stott on March 28, 2014 11:57 AM writes...

I did my PhD on the molecular mechanism of HD with Nobel laureate Max Perutz back in 1993-6. We were trying to testing his "polar zipper" hypothesis, whereby expanded glutamine repeats aggregate into extended b-sheets that are inherently toxic, much like other amyoid-related diseases. And in fact, the mutant protein has been shown to form non-specific pores in cell membranes, just like other amyloid proteins.

That was many years ago, but anyway, I'd still like to share my perspective on this...

The problem I see with the mechanism proposed in this Nature paper is seems too specific for HD and huntingtin, however at least SEVEN other neurodegenerative diseases (SCA1, SCA2, SCA3/MJD, DRPLA, Kennedy's Disease, SBMA, etc.) have been linked to the expansion of glutamine repeats in completely unrelated proteins.

To me this is just too much of a coincidence for each disease to be explained by a different mechanism, and I think any mechanism for HD must be shown to occur in all these other diseases before I would be prepared to believe it.

Just my 2c.

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10. j on March 28, 2014 12:51 PM writes...

Effects are fairly weak in the paper.

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11. Anonymous on March 28, 2014 3:11 PM writes...

@9: I had similar thoughts as you. That's not to say that this isn't one of the contributing factors, but I think there is still more going on.

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12. MoBio on March 28, 2014 3:55 PM writes...

Fig 4 is key--there are very small effects here and although the 'effect on survival' is statistically significant it would not be considered 'meaningful'.

Given the very small effects it might be an interesting exercise to perform a power analysis to see how large a sample would be required to replicate the in vivo results.

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13. Anonymous on March 28, 2014 4:47 PM writes...

So given this is unlikely to be meaningful, I have no idea why on earth this is in Nature.

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14. Anonymous on March 28, 2014 5:10 PM writes...

Oh please, that is exactly why it is. Nature/Science are tabloids, not proper science journals.

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15. Jeff Carroll on March 29, 2014 11:18 AM writes...

I'm a long time HD researcher, and don't find this paper very compelling. The cell data is derived from immortalized neural progenitor cells which have 1000's of transcriptional differences (check out GEO GDS2911). The patient data is consistent with CSE expression being enriched in neurons, compared to other CNS cells - we could easily generate similar looking blots for any neuronally-enriched gene.

The mouse model used in this case, the R6/2, transgenically expresses a tiny fragment of the whole HTT protein - exon 1 of 63 - with a massive CAG-repeat size. They have a rapid phenotype, with a wide range of non-specific pathology (i.e. no one knows what they actually die from - but it isn't neurodegeneration, because they only have about 10-15% striatal volume loss, compared to ~90% in post-mortem human HD patients). For what it's worth, 10's of compounds/transgenes/environmental perturbations have provided similar (or better) levels of rescue in this mouse model. Translation to other models, not to mention people, hasn't been great. Nevertheless, people use it because it's a convenient quick "in vivo" experiment to elevate your paper to Nature, assuming you're Sol Snyder.

Just because I'm sitting here on my soapbox talking to myself, check out the press releases that surrounded the publication of Snyder's other recent HD paper in Nature (on a protein called "Rhes"). Somehow that was also "the" mechanism behind HD when it came out.

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16. Lane Simonian on March 29, 2014 11:38 AM writes...

The release of glutamate which is a common feature of many neurodegenerative disease impedes the uptake of cystine. This limits the production of cysteine. Cysteine itself is easily oxidated. Neither cystine nor cysteine supplementation is likely to make much difference.

Glutathione and hydrogen sulfide are both potent antioxidants that depend upon cysteine. Their depletion is a critical factor in the death of brain cells. When the body's own antioxidant system no longer works one has to turn to external oxidants that readily enter the brain.

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17. Anonymous on March 31, 2014 7:20 AM writes...

@16 Lane: the most frustrating thing about your posts is that you write them as if you know how the entire human body works with absolute conviction. Have you considered that science is about putting forward hypotheses, and asking questions to test them with experiments? Just a tip that might bring more people on your side.

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18. Lane Simonian on March 31, 2014 10:38 AM writes...

I once told one of my critics that I don't need to understand the whole universe of biology; I need to understand the universe of biology that applies to what I am studying which is mainly limited to Alzheimer's disease, but occasionally extends to other neurodegenerative disease. All the comments I make are not based on my knowledge; they are based on the knowledge of others. I will give a couple of studies to back up a few of the statements that I made.

Neuroscience. 1992 Jun;48(4):903-14.
A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion.

Synergistic Depletion of Astrocytic Glutathione by Glucose Deprivation and Peroxynitrite

Dev Neurosci. 1996;18(5-6):391-6.
Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage: implications for neuronal/astrocytic trafficking and neurodegeneration.

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19. Anonymous on March 31, 2014 11:01 AM writes...

^ Thanks Lane. Perhaps adding phrases like "at least one study shows/suggests that" before your otherwise concrete claims, may help distinguish fact from faith, and thus help your credibility.

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20. Lane Simonian on March 31, 2014 11:21 AM writes...

That is good advice. Sometimes, I have multiple studies backing what I am saying and sometimes I only have one or two and I should distinguish between the degree of certainty.

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