Now, however, scientists at the University of Pennsylvania Medical Center have discovered that Lewy bodies may entrap life-sustaining cellular organelles in an important population of cerebellar cortex neurons called Purkinje cells, leading to their death with age. The research opens new questions about the pathogenesis of a number of diseases characterized by the appearance of Lewy bodies, including Parkinson's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), and diffuse Lewy body disease, one of the most commonly occurring dementias after Alzheimer's disease.
The findings may also provide an important new strategy for developing treatments for these diseases, approaches that would aim at prevention or elimination of Lewy bodies. The research team's report appears in the February 1 issue of The Journal of Neuroscience.
"There are many people in the field who see Lewy bodies as useful diagnostic markers, but without significant implications for the health and welfare of neurons," remarks John Q. Trojanowski, MD, PhD, a professor of pathology and laboratory medicine and senior author on the report. "What our study suggests is that this view is incorrect -- these are killer bodies. Lewy bodies are not just innocuous trash that accumulates in the cells over time, but, indeed, may compromise the longevity of neurons."
One reason Lewy bodies have not been looked at more closely as a contributing factor in neurodegenerative diseases is that there has not been an appropriate animal model available for study. Key to the Penn advance was the development of a transgenic mouse that expresses a fusion protein combining a high molecular weight neurofilament protein (NFH) with an enzyme called beta-galactosidase (LacZ). As these NFHLacZ mice age, they develop neurofilament-rich aggregates, called inclusions, in the Purkinje cells that strongly resemble naturally occurring Lewy bodies. The inclusions sequester cellular organelles that produce, package, and ship vital proteins between different parts of the cell. Neurons affected with these inclusions begin to degenerate in the mice at about one year of age and disappear entirely by 18 months of age.
"This mesh of filaments in the cell body seriously interferes with intracellular traffic," Trojanowski explains. "The animals live out their normal lives, but the neurons begin to die at about one year of age. So, the model is similar to Parkinson's disease in the sense that the disease also is a mid-life or late-life disorder."
Trojanowski adds, however, that "this model is not one of Parkinson's disease or ALS or any other particular disease, per se, but of the abnormal inclusion called the Lewy body, known for a long time to be associated with these diseases."
Normal neurofilament proteins are essential to neuronal architecture, creating the matrix that supports the extensions from the cell bodies called axons. Axons reach out as much as a meter in humans to conduct signals to neighboring neurons. However, the excessive aggregation of neurofilament proteins in the cell body, as occurs with Lewy bodies, is abnormal.
The lead author on the paper is Pang-hsien Tu, MD, PhD. Other Penn-based coauthors on the study are Kathryn A. Robinson, BS; Femke de Snoo, MD; and Virginia M.-Y. Lee, PhD, a professor of pathology and laboratory medicine. Joel Eyer, PhD, with the Institut National de la Sante et de la Recherche Medicale Unit 298 in Angers, France, and Alan C. Peterson, PhD, at McGill University in Montreal, Canada, also contributed to the work. Funding support was provided by the National Institutes of Health and the Canadian and French governments.
Dr. John Q. Trojanowski can be reached at (215) 662-6920.
The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $140.5 million in federal fiscal year 1995. In addition, the institution posted the highest growth rate in its research activity -- 11.4 percent -- of the top ten U.S. academic medical centers during the same period. Penn news releases are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the NASW (National Association of Science Writers) Online and SciNews-MedNews sections of the Journalism Forum, a component of CompuServe. Additionally, they are distributed via the electronic news service Quadnet.