An Unexpected Clearance Pathway for Misfolded Proteins in Cell Health Revealed

Category Science

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In a recent study published in Nature Cell Biology, Stanford researchers unveiled a previously unknown pathway for the removal of misfolded proteins from the nucleus, setting the stage for understanding the causes of age-related degenerative diseases. The pathway, regulated by CD kinesin and involving vesicle trafficking, offers therapeutic targets to treat such diseases.

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Misfolded proteins pose a threat to cellular health, as they interfere with normal functions and contribute to age-associated degenerative conditions such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. The mechanisms by which cells eliminate these harmful proteins are not yet fully understood.

A recent study, published on April 20 in Nature Cell Biology, reveals groundbreaking findings by Stanford University researchers. They uncovered a previously unidentified cellular pathway that facilitates the removal of misfolded proteins from the nucleus, where the cell’s DNA is stored, transcribed, and replicated. Maintaining the integrity of these processes is crucial for proper cellular function. This newly discovered pathway offers potential therapeutic targets for treating age-related diseases.

The identified pathway is regulated by CD kinesin, a class of proteins essential for intracellular transport activities

To find the new pathway, researchers in the lab of Judith Frydman, the Donald Kennedy Chair in the School of Humanities and Sciences, integrated several genetic, imaging, and biochemical approaches to understand how yeast cells dealt with misfolded proteins. For the experiments, the team restricted misfolded proteins to either the nucleus or the cytoplasm – the area inside the cell but outside the nucleus. The team visually followed the fate of the misfolded proteins through live-cell imaging and super-resolution microscopy.

Mechanisms for the transport of misfolded proteins between nucleus and cytoplasm involve vesicle trafficking

"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 team identified the "garbage dump" site as the intersection of the nucleus and the vacuole – an organelle full of enzymes for degrading proteins – and showed that misfolded proteins in this "garbage dump" site are moved into the inside of the vacuole for degradation. They also showed that the pathway depends on a class of proteins used to create small vesicles for transporting molecules around cells.

The newly discovered pathway is distinct from the well-known autophagy pathway that facilitates degradation of intracellular proteins

"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 can deal with misfolded proteins in two ways: by refolding them or by eliminating them. A third option is to store them at a specific cellular location.

"While the cell decides whether to refold or degrade proteins, it sequesters them into these membrane-less inclusions," said Frydman, who is senior author of the paper. Inclusions are clusters of misfolded proteins that occur in both the cytoplasm and in the nucleus.

The absence of this clearance pathway reduces cell’s recycling capacity, and has been linked to a multitude of age-related diseases

The team found that the cellular machinery forms small misfolded-protein inclusions in different places within the nucleus and cytoplasm, like tiny garbage dumps, that then migrate toward the boundary between the nucleus and the vacuole, a bigger garbage dump. Eventually, the nuclear and cytoplasmic misfolded protein inclusions line up to face each other, with the nuclear envelope separating them.

Live-cell imaging and super-resolution microscopy were used to determine the fate of misfolded proteins

"The communication back and forth between the nucleus and the cytoplasm was not something we expected at all," said Sontag. "Knocking out one of the vesicle-trafficking proteins told us that this CD kinesin was really necessary for this whole process." .

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