L-arginine stabilizes protein droplets and prevents harmful fibril formation

Protein droplets serve important biological functions within cells, but in neurodegenerative diseases like Alzheimer's, these liquid-like droplets can form solid-like clumps known as fibrils.

So how can scientists prevent fibril formation while still allowing protein droplets to function?

University at Buffalo biophysicists report they have found a way using a naturally occurring small molecule already present in cells. In a study published in Nature Communications, they show that the metabolite L-arginine enhances the stability of protein droplets, protecting them against fibril conversion and preserving their ability to stabilize and assemble microtubules.

The study serves as a proof of principle for identifying small molecules that disrupt fibril formation without affecting droplet function.

"These findings show that protein droplet formation and fibril formation are two separable processes, and that one can be prevented without interfering with the other," says the study's corresponding author, Priya Banerjee, PhD, professor in the UB Department of Physics.

One such protein, Tau, can form droplets that gradually convert to fibrils known as amyloids. These Tau fibrils are one of the hallmark protein clumps seen in Alzheimer's disease, but unlike the well-known amyloid-beta plaques that form outside neurons, they accumulate inside neurons.

This system revealed that fibril formation occurs at the surface of droplets rather than throughout them.

"This means that the inside of the droplet remains liquid-like and functional during fibril formation, so it's possible to keep the droplet intact while simply blocking fibril formation at the surface," says first author, Tharun Selvam Mahendran, a PhD student in Banerjee's lab.

The researchers then added L-arginine, known to prevent protein clumps, to their engineered Tau droplet system. They observed that the droplets stayed liquid-like longer, fibril formation decreased and the droplets continued to assemble microtubules.

"Healthy cells might already be using small molecules like this L-arginine to stabilize the droplets and prevent them from being something toxic," Banerjee says. "So molecules like L-arginine could help guide efforts to develop therapies that target fibril formation in Alzheimer's."

Source:

University at Buffalo

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