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Gene essential to “hallmark” of ALS, identified

Scientists at Stanford have identified a gene key to the formation of a type of toxic protein in amyotrophic lateral sclerosis, a neurodegenerative disease.

There's a collection of neurodegenerative diseases that share a similar tell: protein-dense blobs that amass in the brain. They're typically known as protein aggregates and scientists at Stanford Medicine have identified a critical gene that seems to drive the formation of one of these types of proteins in amyotrophic lateral sclerosis, a devastating neurodegenerative disease that makes physical tasks -- such as walking or even breathing -- extremely difficult.

The gene they've pinpointed, RPS25, specifically contributes to the formation of a type of toxic protein in ALS, also known as Lou Gehrig's disease. It's still early in their research, said Shizuka Yamada, a graduate student at Stanford who led the work, but the future hope is that the gene might lead to some new insights about how to block these toxic protein formations.

A paper detailing the results of the research appears in Nature Neuroscience. Aaron Gitler, PhD, professor of genetics, is the senior author.

As we explain in our release:

The gene, RPS25, codes for a piece of cellular machinery necessary for creating the protein-based gunk that amasses in some forms of ALS and damages healthy neurons. When the gene's activity was experimentally depleted -- in yeast, in neurons derived from patients with ALS and in fruit flies -- Gitler and his team saw levels of the lethal protein drop by about 50 percent across the board.

RPS25 functions outside of the normal realm of protein formation, which is perhaps not surprising, since the proteins it helps create are not normal. RPS25 functions in something called RAN translation, a type of protein manufacturing in the cell that deviates from the conventional protein-making process. From the release:

The exact mechanism of RAN translation and its role in human biology is not clear, but scientists do know that it still depends on [a molecular machine that creates proteins called] the ribosome. To better understand the process, Gitler and Yamada turned to yeast, a simple organism that still has the major proteins and pathways of human cells. One at a time, the researchers decreased the function of individual yeast genes and monitored the fungus' RAN function. When subdued, several genes swayed RAN function, but ... RPS25, stood out. With the gene hindered, production of the toxic protein fell by 50 percent.

What's more, the team also saw that RPS25 was not exclusively involved in the buildup that's found in ALS. When tested in cellular models of two other neurodegenerative diseases that share similar protein aggregate hallmarks -- Huntington's disease and spinocerebellar ataxia -- RPS25 also seemed to play a role in protein build up.

Whether Gitler and Yamada can harness RPS25 as a target for hampering the harmful protein aggregates remains to be seen, but the team says their next step is to test how removing the protein entirely would affect animal models.

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