Huntington's results from mutations in the gene which makes a protein called Huntingtin (Htt). The symptoms are associated with degeneration of various parts of the brain, most importantly, a deep region called the striatum. These facts have been known for many years, but it's unclear how mutant Htt damages the brain. There are various theories, but they've all faced a serious puzzle - Htt is expressed in all adult human cells, but Huntington's only affects some neurones. Why?
A major new paper claims to have the answer : Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity. It also suggests a promising target for drugs that could prevent the damage from occuring.
The authors assemble evidence showing that mutant Htt kills cells only in conjunction with another protein called Rhes. Crucially, Rhes is only expressed in striatal cells. They found that:
- Rhes binds to Htt, but it binds much more strongly to mutant Htt.
- Causing cells to express both Rhes and mutant Htt leads to cell death, but either by its own does not.
- Rhes mediates the binding of mutant Htt to another protein, SUMO, which causes the mutant Htt to become more soluble and therefore more toxic to cells.
Huntington's is a fascinating disorder. The mechanism of inheritance is very distinctive - disease results when a certain section of DNA is too long, and the longer it is, the earlier and more severe the symptoms. And when the pathogenic region is too long, it tends to get even longer during the formation of sperm cells, so the children of fathers with Huntington's often suffer from a more severe, early-onset form. This phenemonon is called genetic anticipation and is unique to Huntingdon's and some similar disorders.
Huntington's is also one of the few disorders which can be accurately diagnosed genetically before the symptoms occur. Anyone at risk of the disease can take a DNA test and know their fate. Perhaps unsurprisingly, most choose not to.
Subramaniam, S., Sixt, K., Barrow, R., & Snyder, S. (2009). Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity Science, 324 (5932), 1327-1330 DOI: 10.1126/science.1172871
4 comments:
I have a very close friend in a Huntington's family. Her father began showing noticeable symptoms that something was wrong in his sixties. He died in his mid 70s.
An Irish-American family, they have 6 offspring-- three males, three females. The eldest son was struck with very bad symptoms in his early fifties and has been living in facilities for the last decade. He is 6'2" and only weighs 110 right now. They have no idea how he has lasted. It's a horrid, horrid disease. He has been kicked out of facility after facility because it's so hard to care for him.
The other sibs, all but my friend, were tested. One other sister and one other brother have the disease. The brother has begun to show a few slight symptoms. He's 49. The sister has a few. She's 64. My friend, who suffered a heart attack and cancer, decided not to get tested. One can understand why.
It's great news that they might be on their way to something for people with this dread genetic disease.
That's very interesting, although I thought eventually the pathology extended out of the striatum into other areas of the brain.
Still, a very promising target. Unfortunately, as bitter experience has taught us with Huntington's, Alzheimer's, Cystic Fibrosis, and various cancers as well as others diseases - a promising target guarantees nothing in terms of the development of therapy.
pj: Actually, the authors do note that the pathology occurs to a lesser degree in the cortex, and they say this fits with the fact that Rhes is expressed at very low levels there.
Whereas it is not expressed at all in the cerebellum, which is spared.
This is the first I have heard of this fantastic news.
My dad has has got it,one of my brothers,and my sister,my other brother won`t have the test.
The testing at St.Mary's Hospital Manchester is a truly miserable affair,involving 18 months of enforced counselling,at which you are told that it is fifty-fifty chance of having Huntingtons. (Strangely, they consider these to be good odds.)then a series of physical and psychological tests after which they take a blood sample.
Then you are told to comeback an agonizing two weeks later for the result.
No exceptions,no discussions would be entered into before the fateful day.
My date was Friday 15th February 2002 at 10:00 am
My darling wife Karen,was with me and made me keep the appointment because that morning I really did not want to know,but with two children to raise
she needed to know the future.
We`were shown to awaiting room,and told to go to another room at 10:00am where we would be told the fateful news
And with the grandest sense of irony,they were late.
They walked though door at 10:13 you can imagine the dark pictures you can conjured up in those 13 mins.
They opened a file, glanced into it and said your clear.
I can think of no other disease in the world that you have to wait 18 months before a diagnosis
Everything surrounding this condition is horrible.
I still take my dad who is 81 and is the oldest patient on their records to a clinic at the hospital and you see young people there with advanced symptoms, it is heartbreaking so this may offer hope for them and there families.
Adrian
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