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 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, neurodegeneration always got worse," says Taylor. "Then when we activated the autophagy system by feeding the flies a drug called rapamycin, neurodegeneration was prevented." The accumulated misfolded proteins were cleared out by the lysosome system. "Then we knew that this system can compensate for the impaired proteasome function, which in itself tells us that the two pathways intersect," says Taylor. "The question was,