Identifying new ways to disrupt the progression of diseases like Alzheimer's or cancer is a primary outcome of biological research. Understanding the fundamental processes that contribute to keep a cell alive or kill it is often a key to unlocking new therapeutic pathways.
Autophagy is an essential part of cellular health, the process by which cells remove and recycle their damaged parts. In autophagy, cells use two layers of fatty molecules called lipids that are coated in proteins to "double bag" these injured components, then consume the sac. The energy generated from its refuse can then power the cell itself.
But many drugs that target the autophagic processes are ineffective (or have side effects) due to gaps in our understanding of various molecular steps in this sequence. A better understanding of the processes that create lipid membranes and correctly populate them with proteins could help identify pathways for breakthrough medical therapies for treating diseases like cancers, Parkinson's and Alzheimer's.
A $1 million grant from the Ono Pharma Breakthrough Science Initiative, which supports bold new ideas in science, will help Cornell researchers explain the cellular cleanup process. Over the next three years, Jeremy Baskin, associate professor and Nancy and Peter Meinig Family Investigator in the Life Sciences in the Department of Chemistry and Chemical Biology and the Weill Institute for Cell and Molecular Biology, will study how chemical modifications to proteins play a powerful role in cell survival.
"This research could help us understand how cells take out their trash-and what happens when that process breaks down," Baskin said. "If we can control this process, we may one day be able to treat many serious diseases more effectively."
Autophagy, derived from the Greek words meaning "self-eating," enables cells to get rid of damaged parts such as broken proteins or worn-out organelles, the specialized structures within a living cell that perform tasks. Autophagy works by wrapping up unwanted materials in the double membrane called an autophagosome, which then fuses with the cell garbage disposal system-the lysosome-for breakdown and consumption.
The failure of autophagic processes is potentially implicated in brain diseases like Alzheimer's, and conversely, cancer cells exploit it for survival and to support rapid proliferation.
Cells often control what proteins do by tagging them with small chemical groups, Baskin said, a process called post-translational modification. One type involves attaching fat-like lipid molecules to proteins.
Only a handful of proteins involved in autophagy are currently known to carry such modifications. But Baskin's team has developed precise chemical tools to search for more-and they've found promising evidence for lipid modifications of many other autophagy proteins. Baskin's research will explore the mechanisms and implications of these discoveries.
Many therapies that target autophagy act in broad and imprecise ways, often causing side effects, Baskin said. If scientists can learn to control these post-translational modification pathways, they could design treatments that adjust autophagy more precisely-turning it up or down as needed. For example, activating autophagy might help clear away toxic proteins in brain diseases. On the flip side, blocking autophagy in cancer cells might make them weaker and easier to kill.
"Post-translational lipidation could be a general control knob for autophagy," Baskin said. "If we learn how to turn it, we could provide new pathways for therapies to treat some really devastating diseases."
The Ono Pharma Foundation supports early-stage scientific research that could lead to major advances in treating disease and managing pain. It looks for scientists with bold ideas and access to the tools to test them.
"What's exciting to me about the support we're getting from the Ono Foundation is that it's enabling us to exploit our expertise in chemical biology methods like bioorthogonal chemistry, which features highly selective chemical tagging reactions inside of living systems without interfering with native biochemical processes," Baskin said. "Combined with other chemical biology tools, we will explore the role of lipid modifications of proteins in controlling autophagy."
Henry C. Smith is the communications specialist for Biological Systems at Cornell Research and Innovation.
