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AT LAST there鈥檚 a glimmer of hope for people with Huntington鈥檚, an incurable
inherited brain disease. Researchers in the US think they may have found the
molecular key to the disease, which might make it possible to develop drugs to
protect the brain.

鈥淭his is really important,鈥� says Gillian Bates, a neurogeneticist at Guy鈥檚,
King鈥檚 and St Thomas鈥檚 School of Medicine in London. The work reveals how the
faulty protein responsible for Huntington鈥檚 kills brain cells, she says, as well
as revealing potential drug targets.

Huntington鈥檚 is caused by a mutated version of the huntingtin gene that
results in the protein having many copies of an amino acid called glutamine. The
normal version of the huntingtin protein has stretches of between 10 and 25
glutamines. But if there are more than 36 glutamines, the protein changes shape
and forms large clumps inside neurons. This kills off these cells in part of the
brain called the corpus striatum, leading to a characteristic loss of
coordination and dementia.

The clumps of huntingtin protein cause cellular chaos by 鈥渒idnapping鈥� other
proteins in the cell. One such protein, called CBP, is essential for relaying
signals that help nerve cells survive. Now two research teams, led by
Christopher Ross and Ted Dawson at Johns Hopkins University in Baltimore, have
discovered why CBP is vulnerable to attack.

Like huntingtin, they say, CBP also contains a short polyglutamine stretch.
These stretches attract each other, allowing huntingtin to grab hold of CBP. To
prove this, the teams created a form of CBP with the polyglutamine bit snipped
out. When they added it to cultured brain cells containing faulty huntingtin,
the altered CBP escaped the clutches of the diseased clumps, and the cells
survived. 鈥淲e can essentially completely block huntingtin toxicity,鈥� says
Ross.

The teams now need to show that this strategy works in living brains, not
just in cell cultures. 鈥淲e have to find ways of showing it in vivo,鈥� says Bates.
If it does work, the discovery will make it possible for researchers to try to
develop drugs to treat Huntington鈥檚 for the first time. Molecules that bind to
the polyglutamine stretches and prevent huntingtin grabbing hold of CBP might
prevent the symptoms developing. 鈥淲e think this is a very feasible and practical
therapeutic target,鈥� Ross says.

Another key discovery is that the genes controlled by CBP are turned off in
diseased cells. This agrees with previous findings that one of the earliest
signs of Huntington鈥檚 disease in mice is a loss of normal gene-regulating
activity. When the researchers made infected cells produce extra CBP, the cells
survived, despite the formation of clumps. Boosting CBP levels might be another
way of combating the disease.

Ross suspects that the kidnapping of proteins by clumps could also play a
role in other degenerative brain diseases, such as Parkinson鈥檚 disease.