Editor's Note: This is part two of a two-part series on new insights into p53 regulation and function. Part one, on p53 regulation in vivo, ran in Wednesday's issue.
The nuclear transcription factor p53 is well known as a tumor suppressor and has attracted considerable attention from both academic and industrial researchers for its potential as a cancer target.
Now, research published in the July 7, 2005, issue of Neuron shows that scientists at Johns Hopkins University School of Medicine and the National Cancer Center Research Institute in Tokyo have bolstered the idea that p53 might be a worthy avenue of investigation in neurodegenerative disorders, as well. In their experiments, they show that p53 might be what links damage in the nucleus and in the mitochondria to Huntington's patients.
Huntington's patients have lower cancer rates than the general population. Senior author Akira Sawa, assistant professor of psychiatry at Johns Hopkins University School of Medicine, succinctly described the central conundrum of clinically targeting p53 for the treatment of Huntington's disease: "Overactivation of p53 may not be good for the brain, but suppression leads to tumors," he told BioWorld Today.
P53 is among many proteins that are up-regulated by mutant huntingtin. P53 also regulates a number of mitochondrial genes, and because Huntington's disease is characterized by both nuclear and mitochondrial dysfunction, the researchers hypothesized that it might be a culprit in the disease.
In cell cultures, the mutant huntingtin protein interacted directly with p53 and up-regulated its levels in the nucleus; the increase was selective and seen in the cortex and striatum - brain areas that are damaged in Huntington's disease.
The team next examined the cellular consequences of the huntingtin-p53 interaction by measuring mitochondrial membrane depolarization, which is a first step toward mitochondrial dysfunction and cell death, in several model cell cultures. Those studies showed that p53 produced mitochondrial membrane abnormalities.
The researchers also investigated effects of the abnormality in p53 in both flies and mice. In a fruit fly model of Huntington's disease, eye damage is one of the typical symptoms caused by mutant huntingtin; deleting p53 suppressed that damage.
In mice that were both p53 knockouts and engineered to have mutant huntingtin, knocking out p53 corrected motor disturbances that the mice otherwise displayed.
The mutation that turns normal huntingtin protein into the mutant protein responsible for Huntington's disease consists of a glutamine expansion; at a certain region of the protein, instead of six to 34 glutamines that the normal protein contains, mutant huntingtin has at least 40 copies of the amino acid. Such a glutamine expansion, known as polyQ expansion, is not unique to Huntington's disease; in fact, there are a number of neurodegenerative diseases caused by glutamine expansions. However, Sawa and his colleagues showed that the expanded glutamine repeat is not sufficient by itself to negatively affect p53.
Mutated ataxin-1 (a protein responsible for another neurodegenerative polyQ disease, spinocerebellar ataxia) with expanded polyglutamine chains had no effect on p53 activity. Sawa and his colleagues are working on elucidating the exact interaction mechanism, though he declined to give details of what the mechanism might be, citing other papers currently under peer review.
The researchers also are working on strategies that might allow their findings to be translated into clinical benefit. Sawa's laboratory is working on two protocols that take into account the special challenges of trying to manipulate a tumor suppressor in a neurodegenerative disease.
The scientists are working on blocking the interaction between mutant huntingtin and p53 without disturbing normal p53 activity; they are testing an inhibitory peptide in both cell culture and animal models.
The second possibility is to search for downstream molecules activated by p53, particularly in the striatum, where Huntington's disease does much of its damage.
Despite the challenges of manipulating a known tumor suppressor for the treatment of Huntington's disease, Sawa hopes that those approaches eventually will translate into clinical benefits; trained as a psychiatrist, as well as a researcher, he said he is "very eager to bring my basic research back into the clinic."