Researchers find new cellular pathway that could help Alzheimer's, Parkinson's, and more

How do cells deal with misfolded proteins?

Using a wide range of techniques, the researchers found that the cellular nucleus, the main center of the cell which houses and processes the DNA, has a "garbage dump" site for misfolded proteins. The site is at the intersection of the nucleus and the vacuole – a cellular organelle that contains enzymes for degrading proteins.

Interestingly, the process is similar for misfolded proteins inside the nucleus as well as outside it. In the cytoplasm, the non-nuclear part of the cell that houses other organelles, the cellular machinery forms small misfolded protein inclusions that begin migrating toward the vacuole.

Not only is this process similar to one found in the nucleus, but the researchers also found the two processes to be constantly interacting with each other since both the protein inclusions finally ended up facing each other with the nuclear envelope – the wall of the nucleus separating them.

While the cytoplasmic inclusion can enter the vacuole easily, the nuclear envelope prevents the nuclear inclusion from doing the same. A few additional experiments later, the researchers concluded that the nuclear inclusion secreted special proteins that resulted in the bending of the nuclear envelope to facilitate the entry of the protein inclusion.

The research experiments were conducted in yeast, but the human cells have a counterpart called lysosome that can perform the same function. The researchers are now working to determine if a similar pathway is also used in human cells and how it is affected by aging.

As the cell ages, the machinery for removing misfolded proteins begins to falter, leading to their build-up inside the cell. This has been found to be the causative agent for diseases such as Alzheimer's, Parkinson's, and Huntington's, to name a few. Understanding the pathway could lead to the development of potential therapeutic targets for these conditions.

The research findings were published in the journal Nature Cell Biology.

Abstract:

Effective protein quality control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we reveal the coordination of nuclear and cytoplasmic spatial PQC. Cytoplasmic misfolded proteins concentrate in a cytoplasmic juxtanuclear quality control compartment, while nuclear misfolded proteins sequester into an intranuclear quality control compartment (INQ). Particle tracking reveals that INQ and the juxtanuclear quality control compartment converge to face each other across the nuclear envelope at a site proximal to the nuclear–vacuolar junction marked by perinuclear ESCRT-II/III protein Chm7. Strikingly, convergence at nuclear–vacuolar junction contacts facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic and nuclear proteins, the latter entailing extrusion of nuclear INQ into the vacuole. Finding that nuclear–vacuolar contact sites are cellular hubs of spatial PQC to facilitate vacuolar clearance of nuclear and cytoplasmic inclusions highlights the role of cellular architecture in proteostasis maintenance.