Huntington’s protein may be kidnapper

Huntington’s disease, a neurodegenerative disorder affecting 250,000 Americans, is

a case of biochemical woe. Tangles of protein collect in brain cells. The tissue

dies, leaving gaping holes in people’s brains. But the protein–dubbed

huntingtin–doesn’t kill cells directly. Instead, it kidnaps another protein

essential for cell survival, researchers report in the March 23 Science.

Christopher A. Ross of Johns Hopkins Medical School in Baltimore and his

colleagues demonstrated in a test tube how huntingtin contributes to cell death.

The scientists were also able to halt the process, saving doomed human cells.

Huntington’s disease is a fatal disorder that begins in midlife and eventually

destroys muscle control and cognitive abilities. It’s caused by a single mutated

copy of the gene for huntingtin. The damaged gene makes a version of the protein

with an unusually long chain of one of its components, the amino acid glutamine.

Instead of folding into a functional protein, chains of glutamine on the mutant

huntingtin molecules stick to each other. These build up in plaques inside brain

cells. Similar plaques collect in the brains of people with Alzheimer’s disease,

but the role of the plaques hasn’t yet been determined.

“Surely, it’s not good for cells to have glop clogging them up,” but the clumps of

huntingtin haven’t appeared to be directly toxic to cells, says Ross. For example,

he notes, the brain cells most likely to die in people with Huntington’s disease

aren’t necessarily the ones containing the protein deposits.

The researchers wondered whether mutant huntingtin proteins might pose indirect

harm by binding to short glutamine chains in other proteins in the cell. This

would pull important proteins out of service and block their normal function.

One candidate protein for this process is known as CBP, or CREB binding protein,

which is central in the biochemistry of cellular survival. The team found that

brain samples from people who had died from Huntington’s disease, as well as mice

with a similar syndrome, had very low amounts of CBP, suggesting that the protein

had been sequestered in huntingtin plaques.

The researchers also grew brain cells that produced abnormal huntingtin and found

that these also kidnapped CBP. When they added CBP molecules that were missing

their strings of glutamine, the molecules didn’t collect in deposits and the cells


Now that the researchers have rescued brain cells in laboratory dishes, says Ross,

their next task is to do the same in living mice.