Emory scientists contribute to study of key regulatory protein in neurodegeneration

A multi-institutional team of scientists has gained important new knowledge about the regulatory role played in Alzheimer’s disease by Pin1, a protein that coaxes other proteins into untwisting. The research is published in the July 31 issue of Nature.

The team of researchers, including a group from the Department of Human Genetics at Emory University School of Medicine, examined slices of brain and found an inverse relationship between the abundance of Pin1 and both the susceptibility of neurons to degenerative damage and the amount of protein tangles. They also found that mice with an artificial disruption of Pin1 develop a neurodegenerative disease that resembles Alzheimer’s.

Lead authors are Drs. Yih-cherng Liou, Anyang Sun, and Kun Ping Lu from Harvard Medical School. Xiaojiang Li, PhD and Zhao-Xue Yu, PhD from Emory School of Medicine studied the degeneration in the brains of Pin1-deficient mice using electron microscopy and immunogold staining. Scientists from the University of Kentucky, the Salk Institute, and Tufts University also contributed to the study.
Scientists studying Alzheimer’s disease and other neurodegenerative diseases resemble detectives poring over a crime scene in a mystery novel. They have identified a couple of suspicious individuals––proteins that form disruptive tangles and knots in the brain. The detectives can piece together how the crime was committed, but they still have questions about some characters standing in the shadows. They want to know not only how, but why.

In Alzheimer’s disease, amyloid precursor protein (APP) and tau form aggregated tangles in the brain: APP outside and between cells, tau within the neurons. “It is clear that both proteins play a role in the Alzheimer’s disease mechanism, but there is some disagreement about which one is more important,” says Dr. Li.

Pin1, part of a class of enzymes called prolyl isomerases, is known to regulate many proteins critical for cell division. Pin1 twists the joints of proteins in specific creaky places, allowing them to change shape. However, it previously was unclear whether Pin1 helped to promote or prevent tangles. Dr. Lu’s laboratory at Harvard had the opportunity to examine the situation in the living brain using Pin1-deficient mice. They had previously found that Pin1 is necessary for proper development of the retina and mammary glands.

Dr. Li’s group joined the effort to analyze the Pin1-deficient brains in a way that was complementary to the biochemical methods used by the Harvard group. They found that the Pin-1-negative mice had degenerating neurons similar to those in Alzheimer’s disease. Dr. Li says it is also important to investigate the connection between Pin1 and APP, which clogs up the brain outside the neurons in Alzheimer’s disease. “The access of many enzymes to tau and APP could be regulated by Pin1,” he says. “And Pin1 regulates many proteins, not just tau and APP. This research is really at the crossroads.” Dr. Li hypothesizes that Pin1 loss of function could contribute to other neurodegenerative diseases like Parkinson’s and Huntington disease.

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