Dangerous Liaisons

NEUROSCIENCE

An unfortunate affinity between two proteins may cause Huntington's disease. The coupling of these proteins--as well as the biochemical consequences--appears to explain the damage to nerve cells and the neurological symptoms characteristic of the disease, according to a new study.

One of the players in this drama is p53, a common protein involved in gene transcription, response to cellular stress, and suppression of tumors. The other player is huntingtin, a protein that is produced in a mutated and abnormally folded form by people with Huntington's disease. The presence of mutant huntingtin increases the amount of p53 in brain cells, report Akira Sawa, a psychiatrist and neuroscientist, and Byoung-Il Bae, a graduate student in neuroscience, both at Johns Hopkins University, and their colleagues (Neuron 2005, 47, 29).

In addition, mutant huntingtin binds to p53 and increases its activity, switching on several genes controlled by p53, according to the researchers. Activation of those genes alters the membrane permeability of mitochondria, the cells' energy-producing organelles. The change in permeability damages the mitochondria and ultimately kills the nerve cells. The researchers confirmed their tissue culture results in animals.

University of Washington, Seattle, neurologists Albert R. La Spada and Richard S. Morrison are impressed by the thoroughness of the researchers' evidence for their proposed mechanism. "By presenting such a broad portfolio of consistent experimental results, the authors made a convincing case that p53 is involved in Huntington's disease progression," they write in a commentary. Prior investigations have pinpointed the mitochondria as a target of the disease, particularly in those regions of the brain affected by the condition, they add. Thus, "the ability of p53 to induce mitochondrial dysfunction made it an appealing candidate for involvement in Huntington's disease."

Sawa's team found that blocking the action of p53 can prevent the mitochondrial damage, suppressing neurodegeneration in animal models of Huntington's disease. That approach isn't applicable in humans, La Spada and Morrison note, because interfering with the ubiquitous p53 "is likely to be laden with too many potentially dangerous side effects to be feasible." On the other hand, they write, "identification of the protein domains that mediate binding between p53 and [mutant] huntingtin could have therapeutic implications."

What might explain the damaging effects of mutant huntingtin and p53 on mitochondria? Sawa and his colleagues speculate that the damage may arise from increased activity of at least two of p53's targets, including Bax and Puma, resulting in depolarization of the mitochondrial membrane. Alternatively, the damage may result from p53's regulation of reactive oxygen species.

Sawa and his colleagues note that p53 may be involved in other neurological diseases, including some forms of Parkinson's disease.