Scientists are reversing an important hallmark of motor neuron disease in the laboratory

Scientists from the Francis Crick Institute and UCL have studied how proteins accumulate in the wrong parts of brain cells in motor neuron disease and have shown how in some cases it might be possible to reverse this.

Amyotrophic lateral sclerosis (ALS), more commonly known as motor neuron disease, is a progressive fatal disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, making patients progressively paralyzed and losing the ability to speak and eat and to breathe.

97% of ALS cases often have an abnormal accumulation of proteins that are involved in the regulation of RNA, so-called RNA-binding proteins, from the nucleus of a motor neuron into the surrounding cytoplasm.

In a new study published today (Aug. 6) in Brain Communications, researchers used laboratory-grown motor neurons from skin cells donated by patients with ALS and showed that it is possible to mislocate three RNAs – reverse binding proteins. The patients who donated cells all had mutations in an enzyme called VCP. This mutation is only present in a small proportion of ALS cases.

They found that the abnormal position of these proteins could be caused by a mutation in the VCP enzyme, which has been shown to increase its activity.

Importantly, the distribution of proteins between the nucleus and cytoplasm returned to normal when the researchers blocked the activity of this enzyme in diseased cells. The inhibitor they use is similar to a drug currently being tested in Phase II cancer studies and also blocks the activity of VCP.

It’s incredibly exciting to show a proof of concept of how a chemical can reverse one of the main characteristics of ALS. We’ve shown this to work for three major RNA-binding proteins, which is important as it suggests that it might work for other disease phenotypes as well. Further research is needed to investigate this further. We need to see if this could reverse other pathological hallmarks of ALS, as well as in other ALS disease models.

Jasmine Harley, author and postdoctoral fellow in the Human Stem Cells and Neurodegeneration Laboratory at Crick.

We were quite surprised at the number of different intron-retaining transcripts that we found in cells with ALS leaving the nucleus and entering the cytoplasm. We did not expect to see this on this scale.

Giulia Tyzack, author and project scientist in the human stem cells and neurodegeneration laboratory

Scientists suspect that the collection of intron-preserving transcripts in the cytoplasm could be a factor in attracting RNA-binding proteins to enter the cytoplasm, although more research is needed to confirm this.

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