"We've now shown that Pin1 [prolyl isomerase] plays a pivotal role in protecting against age-dependent neurodegeneration," says BIDMC cell biologist Kun Ping Lu, M.D., Ph.D., an 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, Ph.D., a collaborator on the study from the Salk Institute for Biological Studies in La Jolla, California. "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 the 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.
The tangles, explains Lu, 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. According to Lu, who together with Hunter first 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 Lu and his colleagues to hypothesize that Pin1 might also be able to prevent tangle formation and resulting neurodegeneration. In this new study, Lu and his coauthors 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."
"Based upon these results, the suggestion that the Pin1 enzyme seems to protect neurons from injury and death renews and sharpens an interest in the control of protein phosphorylation," says D. Stephen Snyder, Ph.D., of the Etiology of Alzheimer's Disease program at the National Institute on Aging, which supported this study. "In so doing, it offers both mechanistic and therapeutic insights useful in developing possible interventions against Alzheimer's disease."
In another twist, adds Lu, his laboratory has discovered that Pin1 is dramatically overexpressed in many human cancers, and that this overexpression is critical for these malignancies to develop in the first place. It would, therefore, appear that certain cancers share common genetic elements with Alzheimer's disease, suggesting that Pin1 may prove to be the missing link between these two seemingly distinct areas of disease, both of which grow much more common with age.
"Pin1 represents a new category of genes whose expression is required to guard against age-dependent neurodegeneration," explains Lu. "We now need to conduct further studies to explore why Pin1 expression is low in certain vulnerable neurons, to understand the relationship between Pin1 and other genes that are known to be involved in Alzheimer's disease, and to find ways to increase Pin1 expression. Answering these questions could lead to the development of therapies to prevent or slow age-dependent neurodegenerative processes."
Study coauthors include BIDMC investigators Yih-Cherng Liou, Ph.D., Anyang Sun, Ph.D., Akihide Ryo, M.D., Ph.D., and Xiao Zhen Zhou, M.D.; Tony Hunter, Ph.D. and Han-Kuei Huang, Ph.D., of the Salk Institute in La Jolla, California; Zhao-Xue Yu, Ph.D., and Xiaojiang Li, M.D., Ph.D., of Emory University in Atlanta; Guoying Bing, Ph.D., of the University of Kentucky; Takafumi Uchida, Ph.D., of Tokohu University, Japan; and Roderick Bronson, D.V.M., of Tufts University School of Veterinary Medicine.
This study was funded by grants from the National Institutes of Health.
Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical, and ranks third in National Institutes of Health funding among independent hospitals in the U.S. The medical center is clinically affiliated with the Joslin Diabetes Center and is a founding member of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox.
Journal
Nature