Arts & Sciences

Research in Action: A new route for cellular waste

  • Researchers identified a pathway to remove compartments that can house misfolded proteins
  • Misfolded proteins can lead to diseases such as Alzheimer’s, Huntington’s and Parkinson’s
  • This new way of removing misfolded proteins could provide a new target for drugs to speed the removal of misfolded proteins and delay or reverse a wide range of diseases that affect the aging population.

In a new study done at Marquette University and Stanford University, researchers have found a novel pathway for removing misfolded proteins from cells. This pathway could provide new drug targets for diseases like Alzheimer’s, Huntington’s and Parkinson’s.

When most people think about protein, they think of powders, shakes and dietary supplements. However, proteins are responsible for everything we do, and for them to function properly, they must first be folded into the correct shape. Much like a paper airplane with a bent wing can’t fly straight, proteins without the proper shape cannot perform their proper respective functions, which can lead to a variety of diseases. This is especially true in the brain where cells are extremely sensitive to misfolded proteins leading to neurodegenerative diseases like Alzheimer’s and others.

Cells have three primary ways of dealing with misfolded proteins: refold them into the proper shape, break them down into their core components to be rebuilt or store them to be dealt with later. When misfolded proteins are stored, they are put into small compartments throughout the cell. These specialized compartments lack a membrane to keep them together but can move about the cell without falling apart.

In a new study published April 20 in Nature Cell Biology, researchers describe a newly discovered pathway for removing these compartments containing misfolded proteins from cells. They utilized several cutting-edge imaging techniques to watch misfolded proteins in different parts of the cell, creating time-lapse movies and 3D reconstructions of the cells. They were able to track the movement of misfolded proteins throughout the cell and found that many of the misfolded proteins end up in compartments near the nucleus — DNA’s storage center. In tracking misfolded proteins from inside the nucleus, they saw that these proteins went to a compartment at the same location.

“This was our first hint that there was something interesting about this location on the nucleus,” said Dr. Emily Sontag, assistant professor of biological sciences at Marquette and co-lead author of the study. “There is communication to different parts of the cell so that all of the misfolded proteins end up in the same location to be degraded.”

While the compartments do line up with each other, the nuclear compartment is still within the boundary of the nucleus and therefore the compartments aren’t able to combine into a single larger compartment.

The team identified the location of these compartments as the intersection of the nucleus and the vacuole — an organelle designed to break down proteins. All the collected misfolded proteins are then shuttled into the vacuole and degraded. While it has been known that the vacuole can break down unwanted proteins, what wasn’t known was that the process was coordinated throughout the cell to collect all the misfolded proteins together at the same location.

The compartments can enter the vacuole through a well-known process called autophagy or “self-eating.” Autophagy can occur in both the nucleus and the cytoplasm, the fluid surrounding the nucleus. What is unique about this new pathway is that it involves a family of specialized proteins that can create membrane bound bags for transporting materials around the cell. Utilizing genetic techniques, the team was able to show that these specialized proteins that can bend membranes to make the transport vehicles can do the same to the nuclear membrane, enabling the nuclear misfolded protein compartment to enter the vacuole and be degraded.

Left – misfolded proteins are collected into compartments that migrate to the area near nucleus-vacuole junctions. Middle – nuclear misfolded proteins also collect into compartments and migrate to the nucleus-vacuole junction. Right – compartments containing nuclear misfolded proteins can exit the nucleus through the nucleus-vacuole junction to be broken down in the vacuole. Image credit: Dr. Emily Sontag

There is a lot of work to do to characterize this new pathway to remove misfolded proteins, and this work is underway at Marquette. Sontag established the Sontag Lab in the Klingler College of Arts and Science’s Department of Biological Sciences in late 2020. Her lab is currently expanding on the role of the specialized membrane remodeling proteins in this process. Graduate and undergraduate students are continuing to use yeast to study the clearance of misfolded proteins and the lab is also using cultured mammalian brain cells to study this pathway.

“While yeast are an incredibly powerful genetic tool for studying misfolded proteins, in order to understand what might be happening in Alzheimer’s and Huntington’s diseases requires us to look at this pathway in brain cells,” Sontag said. “I studied Huntington’s disease using cell models as a graduate student, and I’m really excited to bring this area of research to Marquette. It feels like getting back to my roots.”

The Sontag Lab is also working to define how the communication between different parts of the cell is affected by aging. Many studies have shown that protein quality control measures decline with age, meaning that older cells are not able to remove misfolded and damaged proteins as quickly. This buildup of misfolded proteins can lead to cell death and disease. This new way of removing misfolded proteins could provide a new target for drugs to speed the removal of misfolded proteins and delay or reverse a wide range of diseases that affect the aging population.

“I’m excited to look into how this new pathway of removing misfolded proteins is defective in aged cells and in disease models,” said Sarah Rolli, a Ph.D. candidate in the Sontag Lab. “We are applying this new pathway to other ways the cell responds misfolded proteins to get a better picture of how these misfolded proteins build up in disease.”

Chloe Langridge is a graduate student who is interested in working on cellular communication. “I’m excited to see how this pathway could relate to other communication sites in the cell, as these sites are concentrated misfolded protein hubs,” she said. “I’m interested in seeing how this pathway could be implicated in managing diseased proteins.”

This research was funded by the National Institutes of Health, Way Klingler Faculty Development Awards from Marquette University, Pew Charitable Trusts, and the Gordon and Betty Moore Foundation.