Recent Findings on the Nature of Brain Disorders at the Center for Neurodegenerative Disease

Below are two story ideas based on research at the Center for Neurodegenerative Disease (CNDR) at the University of Pennsylvania Medical Center.

The Tao of Tau: Penn Researchers Implicate Loss of Brain Tau Protein in Newly Categorized Set of Neurodegenerative Diseases

It is fascinating how one little protein can cause so much trouble. Medical researchers have known that the tau protein, found in the neurons - or nerve cells - of the brain, forms fibrous plaques that have a role in Alzheimer's Disease and assorted other brain disorders. Now, researchers at CNDR have demonstrated that the loss of tau characterizes a separate set of devastating, albeit rare, diseases that result in the slow erosion of tissue in the frontotemporal portion of the brain. Their findings were presented in a recent issue of the Annals of Neurology.

Dementia lacking distinctive histopathology (DLDH) is the common diagnosis for an array of dementias marked by the destruction of the same portion of the brain. First described in the 1980s, the Penn researchers have found that these dementias, whether sporadic or inherited, share a common trait: the lack of tau protein. The human brain produces six forms of tau protein, which researchers believe have a role in forming the network of microtubules that serve as a kind of transport system within brain cells. The lack of tau protein may cause these systems to break down, killing off cells in the process.

The researchers are surprised by a complicating development: the tau protein is missing but the tau gene is intact and producing the messages necessary to create the protein.

"As in any good mystery, one solution opens up another set of problems," Vicki Zhukareva, PhD, and Senior Research Investigator at the Penn CNDR. "Somewhere the tau gene's message is getting lost."

The common thread between many degenerative brain diseases is actually a fiber, and CNDR researchers now have a better understanding of how the building blocks of these fibers can clump together and cause illness. The researchers have found that a short stretch of alpha-synuclein, a nerve cell protein, allows the proteins to bunch together in fibrous brain deposits. These brain deposits are indicative of a number of diseases, including Parkinson's Disease and multiple system atrophy, collectively termed synucleinopathies.

"In these diseases, sticky regions in alpha-synclueins allow the proteins to cling to each other and gum up the works," said Benoit Giasson, PhD, postdoctoral fellow in Penn's Department of Laboratory and Pathology Medicine and the CNDR. "This is just a start, but these regions also provide us with an opportunity for therapeutic attack: if we can bind something to this site then maybe the proteins won't be able to form brain deposits."

The researchers found the binding site by comparing alpha-synculein to a closely related molecule, beta-synuclein, which does not form fibers. The sticky region, a mere 12 amino acids out of the 140 that make up the protein, is only found in alpha-synuclein. Their findings were published in a recent issue of the Journal of Biological Chemistry.

What goes wrong to allow a-synuclein to form clumps? According to Giasson, this is one of the "big" questions of neurogenerative disease studies. The exact function of either synuclein protein is not known, however, researchers believe they play a role in the mechanism that directs information across the space between two neurons, called the synapse. CNDR researchers think that plaque-forming occurs through a "seeding" process, at least in test tube experiments.

"We are now beginning to understanding how the protein can form clumps in a test tube under defined conditions, but we still have much work to do to see how they continue to form in live cells," said Giasson. "Likely, seeding occurs when cells are overwhelmed, and establishing the factors that overwhelm cells - thereby leading to synuclein fiber formation - may lead to the development of new therapeutic strategies for Parkinson's and related disease."

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Founded in 1991, the Center for Neurogenerative Disease Research is devoted to developing better diagnostic strategies and effective new therapies - and encouraging the rapid translation of progress at the lab bench to the bedside. John Q. Trojanowski, MD, PhD, and Virginia M.-Y. Lee, PhD co-direct the CNDR, and form a focus point for neurodegenerative research from many disciplines throughout the University of Pennsylvania Health System.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital – the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided $500 million to benefit our community.

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