Rescued. Healthy mitochondria (yellow) are only seen in huntingtin-mutant cells where p53 has been blocked (right).

Important Trigger for Huntington's Disease Found

A single mutated gene results in the uncontrolled movements and mental decline of Huntington's disease. Now researchers have found a link between this gene and the neural damage that underlies the disorder. The link, a protein previously implicated in several cancers, may point to promising targets for treating the disease.

Huntington's disease strikes in middle age and progresses relentlessly for 15 to 20 years. Previous research has shown that, in Huntington's patients, areas of the brain responsible for motor control and cognition contain malfunctioning mitochondria, which supply power to cells (ScienceNOW, 1 July, 2002). Patients with the disease have a mutated version of a protein called huntingtin, but the link between this protein and the damaged mitochondria remained unclear.

According to the new study, a protein called p53, which normally suppresses cell growth, may bridge the gap. Psychiatrist Akira Sawa and colleagues at Johns Hopkins University in Baltimore, Maryland, discovered that the presence of mutated huntingtin dramatically boosts p53 activity in cultured cells. Mice with the mutation had high levels of p53 and mitochondria with leaking membranes and experienced movement abnormalities. Blocking p53 in related mice protected their mitochondria and restored normal movement, the team reports 7 July in Neuron. Since p53 can kill cells if over-activated, the researchers believe huntingtin is damaging mitochondria through its stimulation of the protein.

Sawa acknowledges that p53 itself is an unlikely target for a future treatment: It regulates too many different genes to be safely deleted and can cause cancer if inactivated. More promising, he believes, will be the identification of a gene switched on by p53 that is responsible for neural damage.

Neurogeneticist Al La Spada of the University of Washington, Seattle, agrees that understanding the downstream effects of p53 will be very important. "That's where the therapeutic potential will be," he says.

Related sites
Sawa's home page
La Spada's home page
Huntington's information page - NINDS