Neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease all have one thing in common: the untimely death of nerve cells. New research at Sanford-Burnham shows that these diseases also share the molecular mechanism that leads to cellular death, a finding that identifies new targets for diagnosis and treatment of these diseases. The study, which appeared in today’s issue of Molecular Cell, was led by Dr. Stuart Lipton, director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, and Dr. Tomohiro Nakamura, research assistant professor.Together with their collaborators, Drs. Lipton and Nakamura showed how a gaseous molecule known as nitric oxide (NO) can throw a molecular switch to turn a cell from the path to survival to the path to death.
Scientists have long known that under certain conditions, NO binds to and reacts with caspases, a series of enzymes that are important in cell death. When NO interacts with caspases in this way, it inhibits their activity and prevents nerve cells from dying. But in an entirely unexpected way, the Sanford-Burnham team has now found that an inhibitor of caspases – called XIAP – can also bind to NO. In a process known as transnitrosylation, NO jumps like a “hot potato” from caspases to XIAP. The hot potato inhibits XIAP function, which would normally turn off caspases.
“It’s a double whammy – caspases are activated when NO leaves, but when NO binds XIAP, it also blocks the brake on caspases,” Dr. Lipton explained. “And cells enter the death pathway.”
Why is this mechanism important? Because XIAP transnitrosylation provides a new target for diagnosis, prognosis and treatment of neurodegenerative diseases. According to Dr. Lipton, we can look at brain tissue or fluids from patients to determine if increased transnitrosylation correlates with progression of a neurodegenerative disease.
“We are currently analyzing cerebrospinal fluid and brain tissue from patients with Parkinson’s, Alzheimer’s and other diseases to determine if we can use the NO-tagged proteins as biomarkers for the disease,” said Dr. Lipton, who is also a Harvard-trained neurologist and sees many of these patients in his own clinical practice at the University of California, San Diego.
This mechanism might also have therapeutic potential – if the NO hot potato can be blocked from jumping to XIAP, Parkinson’s, Alzheimer’s and Huntington’s disease might be prevented. To this end, Dr. Lipton’s laboratory is now applying the robotic technology in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics to screen thousands of chemicals for potential drugs that prevent the aberrant or excessive transfer of NO from one protein to another, and thus prevent nerve cell injury and death.
Dr. Nakamura, Dr. Lipton’s collaborator, added “This study is exciting because it directly links NO, a toxic free radical, to cell death machinery in neurodegeneration.”