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Penn researchers link cell's protein recycling systems

Many age-related neurological diseases are associated with defective proteins accumulating in nerve cells, suggesting that the cell’s normal disposal mechanisms are not operating correctly. Now, researchers at the University of Pennsylvania School of Medicine have discovered a molecular link between the cell’s two major pathways for breaking down proteins and have succeeded in using this link to rescue neurodegenerative diseases in a simple animal model. The study appears this week in Nature.

The cell has two internal pathways for breaking down proteins. The ubiquitin-proteasome pathway marks unwanted proteins with ubiquitin tags and shuttles them for rapid breakdown to a complicated structure called the proteasome. The second is the autophagy-lysosomal system, a more general process in which proteins are surrounded by membranes inside the cell for bulk digestion.

“The dogma has been that the autophagy-lysosomal and the proteasomal systems are trains that run on different tracks, with similar purposes, but no point of intersection,” explains senior author J. Paul Taylor, MD, PhD, Assistant Professor of Neurology. “The new finding directly challenges this thinking by showing that one system can be induced to compensate for the other. Cells are able to shift proteins between the systems. We think that this molecular link can be used to benefit a wide variety of neurodegenerative diseases because accumulation of toxic proteins is a common underlying feature of age-related neurodegeneration.”

Taylor and his group study fruit flies in which the proteasome is disabled by a genetic mutation, which results in neurodegeneration. They use the fly eye, a neuron-rich tissue, as a surrogate for the brain because it is easy to visualize. They discovered that making the lysosomal system more or less active dramatically influenced the severity of neurodegeneration.

“We found that whenever we knocked the lysosome system down, neurodegener
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Source:University of Pennsylvania School of Medicine


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