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.