A molecular chaperone that generates adequate amyloid particles for cell-to-cell amyloid transmission

Proteins are the most important biomolecules involved in many biological functions in cells. In your high school textbooks, we have learned that every newly synthesized protein folds into a three-dimensional shape to perform its particular function. However, the paradigm has shifted recently due to the discoveries of intrinsically disordered proteins or proteins that harbor disordered domains that are associated with flexible functions due to having dynamic ever-changing shapes instead of fixed shapes. These interesting classes of proteins along with the misfolded or unfolded structured proteins often tend to form polymers of proteins known as amyloids. Although these proteinaceous assemblies are classically linked with fatal neurodegenerative disorders, examples of their functional roles are not so rare . Recruitment of monomers to the pre-existing amyloids known as seeds accelerates protein aggregation, which is otherwise a slow process. Prions are the self-perpetuating sub-class of amyloids that drive amyloid transmission to neighbor cells through the formation of amyloids templated by preformed aggregates acting as seeds. The prion-like transmission via seeded generation of aggregates is currently thought to be the principal mechanism of amyloid spread for typical non-prion amyloids as well. 

There is a pivotal class of proteins known as chaperones that ensures proper protein folding by preventing or reversing their misfolding or unfolding that might otherwise cause protein aggregation. However, despite all the surveillance, proteins, especially the ones with intrinsic disorders, form amyloids in altered cellular microenvironments. Therefore, there is an interesting class of chaperones in cells classified as disaggregases that try to solubilize already formed aggregates. The proper cellular level of disaggregase is critical for prion-like amyloid transmission as it creates adequate highly-transmissible lower order seeds upon disaggregation of higher-order amyloids that possess limited transmissibility. For our work, we used the yeast disaggregase Hsp104 to understand the dose-dependent remodeling of amyloids by disaggregases in the context of amyloid transmission. For our work via in vitro recapitulation, we used low amounts of pure Hsp104 to mimic the cellular scenario of disaggregase insufficiency during aging. We choose yeast functional prion Sup35 as a model amyloidogenic substrate that shares generic superstructural features with several neuropathological amyloids.

Our results show that the low concentration of Hsp104 can accelerate amyloid formation but can delay their conversion into higher-order aggregates such as fibrils. These alternations in aggregation behavior ensure the abundance of ample fibril precursors as seeds, which otherwise readily convert into less transmissible fibrils. Additionally, the amyloids generated in the presence of low concentrations of Hsp104 showed better potential to seed further amyloid generation and may efficiently carry forward amyloid infection to the recipient cells. Taken together, our data shed light on how disaggregase insufficiency during aging may promote amyloid colonization by creating seeding-efficient highly transmissible amyloids.