Lou Gehrig’s disease
[Source: NIH]

A key gene has been uncovered behind the formation of neuron-damaging protein aggregates that cause amyotrophic lateral sclerosis (ALS) and other neurological diseases. The authors of this study, from Stanford University School of Medicine and with collaborators, have shown that inhibiting the gene’s function curbs production of those aggregates. The gene, RPS25, codes for small ribosomal protein subunit 25. The authors suggest it could be a potential therapeutic target for new drugs for multiple neurodegenerative diseases.

A paper detailing this research was published July 29 in Nature Neuroscience. Aaron D. Gitler, Ph.D., who holds the Stanford Medicine Basic Science Professorship, is the senior author. The lead author is Shizuka B. Yamada, a graduate student in the university’s departments of genetics and biology.

“We know that these protein-rich aggregates are a clear hallmark of ALS,” said Gitler. “But this finding allows us a deeper look into how those aggregates are made, and potentially how we can hinder that process.”

Unconventional translation (repeat-associated non-AUG, or RAN) of C9orf72 repeats generates dipeptide repeat proteins that are known to cause neurodegeneration. These proteins are believed to be the most common cause of both ALS (also known as Lou Gehrig’s disease) and frontotemporal dementia, but they also play a role in other conditions, including Huntington’s disease and spinocerebellar ataxia.

The team did a genetic screen for regulators of RAN translation and identified RPS25. When the team dampened the gene’s activity in yeast, ALS patient-derived neurons, and fruit flies, they saw a drop of approximately 50 percent in the protein’s production. They also tested RPS25 function in human cells modeling Huntington’s disease and spinocerebellar ataxia, two other neurodegenerative illnesses that have protein-aggregate “hallmarks” similar to ALS, said Yamada. Once again, inhibiting the gene helped tamp down the levels of the problem protein.

Nucleotide repeat expansion in C9orf72 appear to be the most common genetic cause of ALS. But other genes have been associated with the development of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, and UBQLN2. The protein aggregates, which comprise ubiquinated proteins, are seen in motor neurons of patients with neurodegenerative diseases.

It is likely that the genetics of ALS are complex. According to current evidence, 5 to 10 percent of ALS cases are familial, but experts believe genetics contribute, directly or indirectly, to a much larger percentage of cases. The number of gene mutations identified is rising both in cases where two or more family members are affected and those that appear to be sporadic.

The prevalence of ALS is about two per 100,000 people on average. The disease is much more prevalent in older people, reaching three-to-four per 100,000 among those in their sixties. But it can also affect people in their 20s and 30s.

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