BreakThrough Digest Medical News |
| Parkinson’s disease protein gums up garbage disposal system in cells Posted: 27 Mar 2013 09:00 PM PDT Clumps of ?-synuclein protein in nerve cells are hallmarks of many degenerative brain diseases, most notably Parkinson’s disease. “No one has been able to determine if Lewy bodies and Lewy neurites, hallmark pathologies in Parkinson’s disease can be degraded,” says Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, at the Perelman School of Medicine, University of Pennsylvania.
“With the new neuron model system of Parkinson’s disease pathologies our lab has developed recently, we demonstrated that these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy system, one of the major garbage disposal systems within the cell.” Macroautophagy, literally self eating, is the degradation of unnecessary or dysfunctional cellular bits and pieces by a compartment in the cell called the lysosome. Lee, also a professor of Pathology and Laboratory Medicine, and colleagues published their results in the early online edition of the Journal of Biological Chemistry this week. Alpha-synuclein (?-syn ) diseases all have clumps of the protein and include Parkinson’s disease (PD), and array of related disorders: PD with dementia , dementia with Lewy bodies, and multiple system atrophy. In most of these, ?-syn forms insoluble aggregates of stringy fibrils that accumulate in the cell body and extensions of neurons. These unwanted ?-syn clumps are modified by abnormal attachments of many phosphate chemical groups as well as by the protein ubiquitin, a molecular tag for degradation. They are widely distributed in the central nervous system, where they are associated with neuron loss. Using cell models in which intracellular ?-syn clumps accumulate after taking up synthetic ?-syn fibrils, the team showed that ?-syn inclusions cannot be degraded, even though they are located near the lysosome and the proteasome, another type of garbage disposal in the cell. The ?-syn aggregates persist even after soluble ?-syn levels within the cell are substantially reduced, suggesting that once formed, the ?-syn inclusions are resistant to being cleared. What’s more, they found that ?-syn aggregates impair the overall autophagy degradative process by delaying the maturation of autophagy machines known as autophagosomes, which may contribute to the increased cell death seen in clump-filled nerve cells. Understanding the impact of ?-syn aggregates on autophagy may help elucidate therapies for ?-syn-related neurodegeneration. ### Co-authors are Selcuk A. Tanik, Christine E. Schultheiss, Laura A. Volpicelli-Daley, and Kurt R. Brunden, all from Penn. This research was funded by the National Institutes of Neurological Diseases (NS053488), the JPB Foundation, and the Jeff and Anne Keefer Fund. 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 $4.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 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 $398 million awarded in the 2012 fiscal year. The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community. Contact: Karen Kreeger |
| Declaring a truce with our microbiological frienemies Posted: 27 Mar 2013 09:00 PM PDT Managing bacteria and other microorganisms in the body, rather than just fighting them, may be lead to better health and a stronger immune system, according to a Penn State biologist. Researchers have historically focused on microbes in the body as primarily pathogens that must be fought, said Eric Harvill, professor of microbiology and infectious disease. However, he said that recent evidence of the complex interaction of the body with microbes suggests a new interpretation of the relationship.
“Now we are beginning to understand that the immune system interacts with far more beneficial bacteria than pathogens,” said Harvill. “We need to re-envision what the true immune system really is.” Harvill said that this reinterpretation leads to a more flexible approach to understanding how the immune system interacts with microbes. This approach should balance between defending against pathogens and enlisting the help of beneficial microbes. While the role that some bacteria play in aiding digestion is better known, microbes assist in improving body functions, including strengthening the immune system and responding to injuries. In some cases, attacking pathogens can harm the beneficial effects microbes have on immune system, according to Harvill. For example, patients on antibiotics have an increased risk of contracting yeast infections and MRSA. “Viewing everything currently considered immunity, including both resistance and tolerance, as aspects of a complex microbiome management system that mediates interactions with the sea of microbes that surround us, many of which are beneficial, can provide a much more positive outlook and different valuable perspectives,” Harvill said. The system that includes bacteria and other microbes in the human body, or the microbiome, is much larger and more integrated into human health than most people suspect, according to Harvill. “The human body has ten times more bacterial cells than human cells,” said Harvill. Adding to the complexity is the adaptive capacity of the human immune system. The immune system can develop antibodies against certain pathogens, which it can reuse when threatened by future attacks from the same pathogen. Harvill, who described his alternative viewpoint in the latest issue of mBio, said that some researchers have not yet accepted this broader approach to the immune system. “Among immunologists or microbiologists this is an alien concept,” said Harvill. “It’s not part of how we have historically looked at the immune system, but it’s a useful viewpoint.” Other researchers who study plant and nonhuman biology are already starting to embrace the concept. For example, plant biologists are beginning to recognize that viruses can help plants resist drought and heat. “Within nonhuman immunology, this is not an alien concept because they have seen many examples of beneficial relationships between the host and its microbial commensals,” Harvill said. Harvill said adopting this new perspective could be the first step toward new medical treatments. “This new viewpoint suggests new experiments and results will published,” said Harvill. “And, hopefully, the concept becomes more and more mainstream as supporting evidence accumulates.” ### The National Institute of General Medical Sciences supported this work. Contact: Matthew Swayne |
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