Major Huntington's Disease Puzzle Solved

Huntington's Disease is a genetic neurological disorder. Symptoms most commonly appear around age 40, and they progress gradually from subtle movement abnormalities to complete loss of motor control and dementia. Psychiatric problems, especially depression and irritability, are also common and may be the first signs. Treatment consists of medications to mask some of the symptoms. Singer Woodie Guthrie is perhaps the disease's best known victim: he ended his days in a mental institution.

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.

This looks to be a very important addition to the literature on Huntington's. The implication is that a drug which could prevent Rhes from SUMOylating mutant Htt would halt the progression of the disease (although it would presumably not reverse any damage which had already happened.) This is the kind of powerful explanation that neuroscientists who study psychiatric disorders dream about. Maybe in 50 years we will have a similar understanding of schizophrenia - maybe.

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