Two Enzymes Play Key Role Against Stress Granules in ALS, Other Neurological Disorders, Study Finds

Two Enzymes Play Key Role Against Stress Granules in ALS, Other Neurological Disorders, Study Finds

Two enzymes called USP5 and USP13 were found to have an important role in fighting back against toxic “stress granules,” a study reports.

The study, titled “Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities,” and published in the Journal of Cell Science, adds a new layer of knowledge on the mechanisms involved in the formation of toxic aggregates.

Given the key role of stress granules in the progression of several neurodegenerative disorders, this insight opens potential therapeutic avenues for several diseases, including amyotrophic lateral sclerosis (ALS).

Stress granules, as the name suggests, are small clumps of proteins and RNA molecules formed when cells are under stress. RNA is the template molecule, created from the reading of DNA information, that generates proteins.

These can not only become toxic to cells but can also change the way cells behave by scavenging important mediators of cellular processes.

USP5 and USP13 are two enzymes belonging to a large family responsible for cutting down ubiquitin chains inside stress granules. These ubiquitin compounds, common in cells, are required for normal protein balance.

Using temperature to promote cellular stress similar to what occurs in neurodegenerative diseases, the team, led by researchers at Tokyo Institute of Technology, evaluated the specific role of USP5 and USP13 in the process.

They found that, upon heat stress, both USP5 and USP13 are recruited to stress granules and regulate the disassembly of these structures during the following recovery period. But in the absence of these enzymes, the cells would not be able to undergo this healing process, accumulating even more ubiquitin chains in a faster assembly of heat-induced stress granules.

In the presence of USP5 and USP13, the percentage of cells with stress granules fell to 14% during the recovery period. In contrast, in the absence of these two enzymes, about 60% or more of the cells had stress granules.

Although the team still does not know the exact mechanism involved in this process, they suggest that USP5 is needed to cut the free ubiquitin chains and USP13 cuts the ubiquitin chains bound to proteins.

“We concluded that both reactions are required for the efficient destabilization of stress granules,” Toshiaki Fukushima, a researcher at Tokyo Tech and co-author of the study, said in a press release.

Supported by these results, the researchers believe that “artificial deubiquitinating enzymes” are an attractive therapeutic option that could have a profound clinical impact for several neurodegenerative disorders. Development of such innovative enzymes could represent a new targeted therapeutic strategy that could be achieved within five years, Fukushima said.

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