Genetic researchers connect ALS suppression to the protein REST

Genetic researchers connect ALS suppression to the protein REST

In a groundbreaking study, researchers from Tohoku University and Keio University have discovered a shared pathway that contributes to the development of amyotrophic lateral sclerosis (ALS). This common mechanism, the suppression of the UNC13A gene, has been linked to various genetic forms of ALS.

ALS is a condition that causes the gradual breakdown of nerve cells responsible for controlling movement. Over time, muscles weaken, making simple tasks such as speaking, eating, or breathing more difficult. The new research may not solve everything, but it could bring science closer to treatments that help a larger number of ALS patients.

The study, published in the journal Cell Reports, reveals that four different proteins known to play a role in ALS have a common effect: they disrupt the process by which cells handle their RNA, leading to the suppression of the UNC13A gene. This overactive REST turns down the UNC13A gene, leading to gene suppression and keeping it from doing its job.

UNC13A is crucial for nerve cells to communicate effectively. It helps in the formation of synaptic active zones, which are essential for proper neurotransmitter release and motor neuron communication. The suppression of UNC13A manifests as ALS-associated motor neuron degeneration and may contribute to phenotypic variability such as bulbar-onset disease, cognitive impairment, and shorter survival.

The signs of high levels of REST and lower activity from UNC13A have been found in both lab experiments and in tissue samples from ALS patients. Loss or mislocalization of RNA-binding proteins (RBPs) such as TDP-43, FUS, MATR3, and hnRNPA1 leads to REST-dependent transcriptional repression of UNC13A, causing reduced UNC13A protein and impairing synaptic active zones.

The discovery of this shared pathway could pave the way for the development of treatments that help more patients, not just those with one specific kind of ALS. Potential treatments targeting this shared pathway include restoring UNC13A expression, using lithium carbonate in clinical trials, and developing antisense oligonucleotides (ASOs) aimed at correcting aberrant splicing or increasing UNC13A function.

This research offers a possible way to reach many pieces of the ALS puzzle at once, which could bring science closer to treatments that help more people live longer and better. For those watching loved ones go through ALS, this discovery represents a significant step forward, offering a measure of hope for the future.

1. This groundbreaking study could revolutionize the field of medical conditions, focusing on chronic diseases like ALS.
2. The discovery of a shared pathway in ALS could also impact other neurological disorders.
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