Missing Enzyme Found to Lead to Alzheimer?s Disease Symptoms
La Jolla, CA – An enzyme studied by scientists for years can prevent tangles of proteins from forming in the brain's nerve cells – as occurs in patients with age-dependent Alzheimer's disease, according to a study by investigators at the Salk Institute, Beth Israel Deaconess Medical Center and Harvard Medical School.
These findings on the enzyme called Pin1 appear in the July 31, 2003 issue of the journal Nature, and offer new insights into Alzheimer's disease and other neurodegenerative disorders. They mark one of the most significant genetic relationships found to date with Alzheimer's disease, and may eventually lead to new therapies to help prevent and treat these devastating conditions.
"We've now shown that Pin1 (prolyl isomerase) plays a pivotal role in protecting against age-dependent neurodegeneration," says Beth Israel cell biologist Dr. Kun Ping Lu, associate professor of medicine at Harvard Medical School and the study's senior author. "This makes a convincing case that this enzyme should be taken into consideration in future studies of Alzheimer's disease."
"This is an exciting advance in our understanding of neurodegenerative diseases," adds Tony Hunter professor of molecular genetics at the Salk Institute and discoverer (with Lu) of Pin1. "When we first began studying Pin1 we knew that all animal cells had this enzyme and that it was likely to be important, but we had no idea that it would turn out to play a critical role in keeping neurons healthy in the brain."
The most common cause of dementia in older people, Alzheimer's disease affects an estimated 4 million individuals in the U.S., a number that is expected to increase significantly in coming years as the baby boomer generation ages. Ever since autopsies of Alzheimer's patients first uncovered bunches of "tangles" in the brain's neurons, investigators have studied the possibility that overexpression of a gene was responsible for this turn of events. This new research represents the first genetic evidence that age-dependent neurodegenerative diseases develop, instead, because a gene is absent.
Tangles are bunches of a long, stringy protein called tau. In healthy brains, tau serves to both assemble and support the "scaffolding" systems that give neurons their structure and function. As part of their normal function, phosphates are routinely added and removed from tau through processes known as phosphorylation and dephosphorylation. However, in certain neurodegenerative conditions, such as Alzheimer's disease, tau becomes burdened with excess phosphate molecules, causing the protein to change shape and cluster into fibers. These fibers become tangled and knotted, forming rigid structures that eventually lead to the destruction of the affected neurons in certain regions of the brain, resulting in symptoms of dementia.
Enter the Pin1 enzyme. Since Lu and Hunter identified the enzyme in 1995, test tube studies found that Pin1 has the ability to promote dephosphorylation of tau, restoring it to its original shape. This finding led the scientists to hypothesize that Pin1 might also be able to prevent tangle formation and resulting neurodegeneration. In this new study, the researchers tested this hypothesis by comparing Pin1 expression profiles in different brain regions of both healthy individuals and patients with Alzheimer's disease. The investigators also created a knockout mouse model to study the consequences of removing the Pin1 gene altogether.
Their results clearly indicated that Pin1 is required to ensure that neurons function normally, and to prevent them from falling prey to age-related neurodegeneration. "Our findings showed that Pin1expression inversely correlates with neuronal vulnerability to degeneration in normal brains, and with the actual formation of tangles in patients with Alzheimer's," says Lu. "Furthermore, we found that in the Pin1 knockout mouse, the removal of the Pin1 gene alone was sufficient to cause many age-dependent neurodegenerative changes."
This study was funded by grants from the National Institutes of Health.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.