Peptide Encourages Cells to Eat Their Trash, and Viruses
Autophagy, Beth Levine told BioWorld Today, "can very simply be understood as a cellular housekeeping mechanism."
But that simplicity is deceptive. Autophagy's housekeeping, it turns out, sits at a crossroads that gives it a role in many diseases. In the Jan. 31, 2013, issue of Nature, Levine, who is at the University of Texas Southwestern Medical Center, and her colleagues published data in support of the notion that inducing autophagy could be helpful in both neurodegenerative and infectious diseases.
Autophagy is the process by which cells break down relatively large cell components that are unneeded or damaged. By and large, the process deals with items that are too big to be dealt with by the cell's proteasome, and not damaged enough to trigger apoptosis.
That includes damaged and misfolded proteins. It also clears out damaged organelles. The process, Levine pointed out, is "especially useful in cells that don't divide and so accumulate garbage," such as neurons, and so smoothly working autophagy appears to be important in preventing neurodegenerative disorders.
"There's been a lot of interest in the concept that we should up-regulate autophagy, but there haven't really been specific ways to do that," Levine said. "This study demonstrates that a protein that specifically increases autophagy can be beneficial."
Drugs that increase autophagy have been identified in screens, but candidates to date have had a number of other effects as well. The same is true of starvation, which is a reliable way to induce autophagy as cells essentially triage, cannibalizing less important proteins for the benefit of keeping critical systems working.
Another use for autophagy is to respond to intracellular infections, both bacterial and viral. (See BioWorld Today, Nov. 29, 2004.)
Bugs, of course, are no slouches in subverting the mechanisms that cells have evolved to deal with them. "A lot of successful viruses have ways to block autophagy," Levine said. She and her team reasoned that one way to identify critical components of the autophagy machinery would be to look at where viruses attack it.
One autophagy-blocking protein is the HIV protein Nef. It binds to beclin, a protein that induces autophagy in response to cellular stresses.
In their studies, they looked at the exact part of beclin that Nef binds to an 18-amino-acid stretch. The team created an engineered version of those 18 amino acids, and connected that peptide to another peptide that served as a delivery vehicle, ferrying the beclin-1 peptide into cells. The construct, Levine said, turned out to be both necessary and sufficient to induce autophagy.
The team next looked at how the engineered peptide induces autophagy, and discovered a novel role for its binding partner, the protein GAPR-1, in autophagy. GAPR-1 normally holds beclin in a part of the cell where it cannot induce autophagy. The peptide appears to work at least in part by freeing beclin from GAPR-1's grasp, though the authors noted in their paper that "other unknown mechanisms may also contribute to the autophagy-inducing activity" of the peptide.
Levine and her team next tested the peptide in models of both neurodegenerative disease and infections. Autophagy destroys misfolded proteins in polyglutamine disorders. In that family of neurodegenerative disorders, proteins aggregate or clump together because they have an expanded glutamine repeat.
Huntington's disease is the most famous of the polyglutamine disorders, and Levine and her team looked at the effects of their peptide on aggregates of mutant huntingtin. In cell cultures, treatment with the peptide did not clear pre-existing large aggregates of huntingtin. But it did clear both smaller aggregates and soluble protein, preventing new aggregates from forming and growing.
Treatment with the peptide also reduced mortality in mice infected with either chikungunya or West Nile virus.
Levine noted that although "it's a long way from what we have now to a drug," her team plans to conduct further the preclinical studies that are the early steps toward a drug.
While she is interested in autophagy's potential in both neurodegenerative and infectious disease, one area that Levine will stay away from is aging, per se. That's not because autophagy does not play a role in aging. On the contrary. Autophagy "is essential for life span extension it declines with aging, and that probably contributes to aging."
But "aging studies take too long," she said. "Even in mice."
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