Scientists from Stanford University say they have discovered a previously unknown cellular pathway that clears misfolded proteins, a finding that could be a target for the treatment of age-related diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.
The new research, published in Nature Cell Biology, says that the new pathway removes the misfolded proteins from the nucleus where a cell stores, transcribes, and replicates DNA, a critical process to prevent them from interfering in normal cell function. Investigators, led by Judith Frydman, PhD, professor of genetics at Stanford, discovered the pathway via the integration of genetic, imaging, and biochemical approaches to understand how yeast handled misfolded proteins. For their experiments the team restricted misfolded proteins to either the nucleus of cytoplasm then visually followed what happened to them via live-cell imaging and super-resolution microscopy.
“The first exciting thing was that we actually found that there’s communication between the nucleus and the cytoplasm,” said Emily Sontag, the co-lead author of the paper and a former postdoctoral student in the Frydman Lab. “So they’re telling each other, ‘We both have a lot of misfolded proteins; let’s coordinate to send them here to this garbage dump so that they can be removed.’”
The so-called “garbage dump” site identified by the team was at the intersection of the nucleus and the vacuole—and organelle containing enzymes that degrade proteins. Via their observations, the researchers showed that the misfolded proteins are moved into the vacuole for degradation. In addition, the team showed that the pathway depends on the class of proteins used to create small vesicles for transporting molecules within cells.
“Tying that particular family of proteins and this aspect of vesicle traffic biology to protein clearance gives us a new way to look at Alzheimer’s, Parkinson’s, Huntington’s—all these neurodegenerative diseases,” said Sontag.
Cells handle misfolded proteins by either refolding them or eliminating them, with a third option of storing them a specific location with the cell. The researcher found that the misfolded protein garbage dump site within the cells is shared by both the nucleus and the cytoplasm. While the cell is deciding how it wants to handle the proteins is sequesters them in membraneless inclusions—clusters of misfolded proteins that occur in both the nucleus and cytoplasm. These inclusions form in different places in the nucleus and cytoplasm eventually migrating the boundary between the nucleus and vacuole. These inclusions will line up to face each other with the nuclear envelope separating them.
“The communication back and forth between the nucleus and the cytoplasm was not something we expected at all,” said Sontag. “Knowing that those two compartments can kind of work together to clear garbage from everywhere was really awesome.”
Frydman said this finding indicated that while the management of the misfolded proteins in the nucleus and cytoplasm are distinct, this activity also shows they are also coordinated between the two. “What is really cool is that each compartment moves their misfolded proteins to the site where the nuclear envelope meets the vacuolar membrane,” she added.
The Stanford team conducted this early research on yeast cells since they are easy to create and reproduce quickly. A possible next step of inquiry is to find whether the activity in this new pathway in yeast is also used in mammalian cells to clear disease-related misfolded proteins. Other suggested avenues of research based on the findings is to determining how the communication between the nucleus and cytosol occurs in the pathway, as well how the pathway may change as humans age.
“There’s a lot of evidence that this process for dealing with misfolded proteins slows down with age,” said Sontag. “So, as time goes on, aged cells are not able to remove all that garbage as quickly or as efficiently, and misfolded proteins build up more and more inside the cell.”
“We showed that nuclear and cytoplasmic quality control pathways communicate via the nuclear envelope, a structure that is impaired by aging and by neurodegenerative disease,” said Frydman. “Many progeria mutants, which cause premature aging, distort the nuclear envelope. This work really is a game changer in finally bringing a new way to understand, and hence cure, a wide range of terrible diseases that affect an increasingly aged population.”
