Sci. Aging Knowl. Environ., 13 July 2005
Study fingers p53 as an accomplice in Huntington's disease
The protein huntingtin leads a molecular conspiracy that destroys brain cells and kills patients with Huntington's disease, and now researchers have captured one of its minions. The new study identifies the cancer-fighting protein p53 as one of huntingtin's gang, a discovery that might help researchers devise treatments for the incurable disease.
Like brain illnesses such as Parkinson's disease and Alzheimer's disease, HD probably stems from misfolded proteins. HD patients fashion a version of huntingtin with extra copies of the amino acid glutamine, which distort the protein. The more copies, the sooner the disease erupts. Researchers aren't certain how elongated huntingtin undermines patients' muscle control, steals their faculties, and spurs rages and emotional swings (see "Huntington's Case Study"). Several studies suggest that faulty huntingtin shorts out mitochondria, the cell's energy generators, presaging the neuron's death. Huntingtin also causes trouble in the nucleus: As more huntingtin accumulates there, cells are more likely to perish. Psychiatrist Akira Sawa of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues hypothesized that the protein p53, a molecular guardian that stymies cancer and determines whether damaged cells live or die, might link lengthy huntingtin to nuclear and mitochondrial problems. The researchers note that p53 controls many nuclear genes that operate the mitochondria and that it gloms onto abnormal huntingtin, suggesting that the proteins collaborate.
To link huntingtin and p53, the researchers gauged p53 quantities in neuron precursor cells engineered to produce faulty huntingtin. The cells carried about 10 times as much p53 as did controls that manufactured normal huntingtin. Brain tissue from HD patients also harbored extra quantities of p53. Mitochondria faltered in mouse brain cells altered to produce defective huntingtin. However, the organelles remained vibrant if the cells couldn't make p53. Neurons without the protein were also more than twice as likely to survive as were p53-fashioning cells.
The team next explored the p53-huntingtin connection in lab animals. In fruit flies modified to manufacture faulty huntingtin, eye neurons degenerate. Fewer cells perished if the flies lacked p53. Previously, researchers found that mice that churn out flawed huntingtin behave unusually. For example, a mouse typically spreads its hind legs when picked up by the tail. Altered mice clasp their rear paws together, and they spend inordinate amounts of time scurrying in circles. The researchers found that animals that made faulty huntingtin but lacked p53 behaved like normal rodents. Overall, the results suggest that defective huntingtin boosts output of p53, which in turn triggers cellular damage and behavioral abnormalities, says Sawa. Because p53 guards against cancer, tampering with it would be unwise. However, preventing p53 from attaching to huntingtin might ease HD symptoms without disastrous side effects, he says.
By assembling data from cell cultures, lab animals, and patients, the study makes a compelling case that p53 is huntingtin's accomplice, says neurogeneticist Albert La Spada of the University of Washington, Seattle. Now researchers need to determine how p53 fouls up mitochondria and sparks other ill effects. That work might reveal other targets for drugs and finally allow doctors to break up the HD plot.
July 13, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150