The Hope Center Program on Protein Misfolding and Neurodegeneration

David M. Holtzman, M.D., and Allison M. Goate, Ph.D., Directors

The mental impairments and muscular disabilities so characteristic of diseases like ALS (Lou Gehrig's disease), Parkinson's and Alzheimer's result from the degeneration of nerve cells. These neurodegenerative diseases and others like them afflict millions of people in the United States, and because these diseases are largely associated with aging, their incidence is expected to rise as the aging population grows. Most disheartening is that at present no treatments have been able to delay the onset of disease onset or slow their progression.

The Hope Center Program on Protein Misfolding and Neurodegeneration aims to find diagnostic tools and effective treatments for neurodegenerative diseases by investigating their underlying cause. This new interdisciplinary program is part of the larger Hope Center for Neurological Disorders.

"It has become clear in just the last ten years that many neurodegenerative diseases are disorders of protein folding," says co-director David M. Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of Neurology. "Normally soluble proteins misfold, become insoluble with age and aggregate, leading to malfunction and death of nerve cells."

The discovery that the clumping together or aggregation of proteins is a common feature of neurodegenerative disorders could now be an important catalyst for progress toward cures. "If we uncover new information about one of these disorders, or if we find some treatment that helps in one disease, it may be applicable to all the others," says co-director Alison M. Goate, Ph.D., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and a professor of genetics and of neurology. "Our program creates a synergy that will enable us to address these hypotheses in multiple diseases more quickly."

Each neurodegenerative disease stems from aggregation of a different protein: Alzheimer's from the proteins amyloid beta and tau, Huntington's from huntingtin, Parkinson's from alpha synuclein and so on.

These proteins are produced by most cells — some in nerve cells, some in other cells of the body. Researchers don't yet know the normal function of many of these proteins, but they now recognize that when these proteins become incorrectly assembled — what scientists call misfolded — they can form deposits within the nervous system that can lead to degeneration of nerves.

"There's a common underlying mechanism, but a unique pathology and unique set of symptoms associated with each protein and where it deposits," Goate explains. "The group we've put together in this center has neurodegenerative disease and protein aggregation as its common theme, but we're approaching protein aggregation from several different angles to fully understand its role."

The Hope Center Program on Protein Misfolding and Neurodegeneration is part of the larger Hope Center for Neurological Disorders, which is dedicated to improving the lives of people living with neurological disorders and is directed by Mark P. Goldberg, M.D., professor of neurology and of neurobiology. Deputy director of the Hope Center is Anneliese Schaefer, Ph.D., assistant professor of neurology.

Labs now within the Program on Protein Misfolding and Neurodegeneration have already established a strong tradition of research on Alzheimer's disease. Their research has ranged from identifying the genes contributing to protein aggregation — to new techniques for measuring the abnormal protein in blood and spinal fluid — to looking for ways to break up the protein deposits.

In nearly every neurodegenerative disorder, there are rate autosomal dominant forms of the disease where an alteration in the gene coding for a particular protein is the source of the change in protein structure that causes its aggregation. But the latest research shows that variations in other genes can also contribute to this process, and the program will seek the range of genetic factors that influence risk for neurodegenerative diseases.

The program will also study the normal function of the aggregating proteins and study how the aggregation of these proteins damages axons and synapses of nerve cells and ultimately kills them.

"We have an outstanding group of people at the School of Medicine working on this topic," Holtzman says. "But bringing us all together in the new facility will help us better organize our work. We will be able to cover all phases of research relevant to this topic, from the test tube to the human patient."