Single Mechanism Seen To Underlie Group Of Neurodegenerative Diseases: Mutant Proteins Form Insoluble Masses In The Nuclei ...( at some point will begin to shut down n...)

at some point will begin to shut down nuclear processes critical to the cell's survival," says Randall N. Pittman, PhD, an associate professor of pharmacology and senior author on the Neuron paper, which deals with Machado-Joseph disease. "What's emerging from these studies is a recurring theme. In several important neurodegenerative diseases, we are seeing these proteins aggregating abnormally and forming insoluble complexes in the nuclei of certain brain cells. It's a pathological hallmark that suggests that a single disease mechanism may underlie this group of afflictions."

The new results suggest several directions for future research, according to Pittman. Because the proteins involved are produced in cells throughout the body, including the brain, one question scientists would like to be able to answer is why the aggregations occur only in selected populations of neurons. How and why do the proteins accumulate in the nucleus, instead of passing back and forth into the cytoplasm across the nuclear membrane? How is the mutant protein able to recruit the normal protein -- and perhaps other nuclear proteins -- into the inclusions? And what are the specific links between the aggregates and neuronal dysfunction and death? Potential therapies for the diseases could be pursued along each of these lines of inquiry.

The lead author on the Neuron paper is former Penn research associate Henry L. Paulson, MD, PhD, now at the University of Iowa. With Pittman, coauthors at Penn include Matthew K. Perez, MS; John Q. Trojanowski, MD, PhD, a professor of pathology and laboratory medicine; Sonal S. Das, BS; and Kenneth H. Fischbeck, MD, a professor of neurology. Coauthors at other institutions include Y. Trottier and J.-L. Mandel at the Institut de Genetique et de Biologie Moleculaire et Cellulaire, France; and S.H. Subramony and P. Vig at the University of Mississippi, Jackson.

Funding for the work was provided by the National Institutes of Heal
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Contact: Franklin Hoke
hokef@mail.med.upenn.edu
215-349-5659
University of Pennsylvania School of Medicine
7-Aug-1997

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