Hydration of proteins for an early detection of neuro-degenerative diseases

A Study by a team of Indian scholars has found that “Hydration dynamics” of proteins plays a pivotal role in the aggregation of several proteins which is a preliminary step towards various neuro-degenerative diseases. This aggregation process could be spotted early by detecting altering water network dynamics and modulated using inactive substances that serve as the vehicle or medium for a drug or other active substance.

Understanding debilitating neuro-degenerative diseases at the molecular level is crucial to find treatments or solutions for them. A phenomenon called ‘liquid liquid phase separation’ (LLPS) underlines the formation of cells organelles like P bodies, nucleolus which are membrane-less compartments in the cytoplasm of cells.

LLPS, a self-aggregated system, is an intermediate step during the formation of the stable protein aggregates. This process plays an important role in the formation of cells organelles like P bodies, nucleolus which are membrane-less compartments in the cytoplasm of cells.

It may be noted that Protein aggregation is the main hallmark of neurodegenerative diseases. Many proteins found in pathological inclusions are known to undergo liquid-liquid phase separation.

When multivalent proteins interact they undergo rapid transformation from small complexes to large polymeric assemblies with increase in protein concentration. This dense phase often resembles liquid droplets exhibiting higher protein density and weaker molecular motion than the surrounding medium.

This process, initiated through liquid phase transfer, plays a crucial role in inducing human diseases, especially age-related neuro-degenerative diseases like Alzheimer’s disease, Parkinson’s disease and cataract. Therefore, understanding the process of phase separation at a molecular level has become an emergent area of research in the molecular biology fraternity.

Scientists at the S.N Bose National Centre for Basic Sciences, an autonomous institute of the Department of Science and Technology (DST) have explored how the hydration of proteins gets altered as LLPS sets in. The researchers have spotted the crucial role of water in Liquid liquid phase separation which holds the key to neuro-degenerative diseases.

They found that some excipients or inactive substances that serve as the vehicle or medium for a drug or other active substance like sucrose can stabilise LLPS while some can inhibit it.

Thus the aggregation process of these diseases could be modulated by altering water network dynamics using these excipients.

In a paper published in J. Phys. Chem. Lett the scientists, under the leadership of Prof. Rajib Kumar Mitra, examined four excipients —arginine, glucose, ubiquitin, and bovine serum albumin. Some excipients like sucrose were found to stabilize the LLPS process while Bovine Serum Albumen (BSA) was found to inhibit the process.

Their experiments have identified that both protein and excipient hydration are important in regulating the LLPS process. Monitoring a change in hydration could therefore act as a potential marker for an early and easy detection of LLPS onset.

The idea is this – if the aggregation process could be spotted early by detecting altering water network dynamics, it could be modulated using inactive substances that serve as the vehicle or medium for a drug or other active substance.