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 as patients become increasingly paralyzed and shed. the ability to speak, eat and breathe.

A common phenomenon in 97% of ALS cases is the abnormal buildup of proteins involved in RNA regulation, called RNA binding proteins, from the nucleus of a motor neuron to the surrounding cytoplasm.

In a new study published in Cerebral communications today (August 6), the researchers used laboratory-grown motor neurons from skin cells donated by patients with ALS and showed that it was possible to reverse the incorrect localization of three protein-binding proteins. ‘RNA. The patients who donated cells all had mutations in an enzyme called PCV. This mutation is only present in a small proportion of ALS cases. *

They found that the abnormal location of these proteins can be caused when the VCP enzyme is mutated, which has been found to increase its activity.

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

“Demonstrating the proof of concept of how a chemical can reverse one of the key characteristics of ALS is incredibly exciting,” says Jasmine Harley, author and postdoctoral researcher at Crick’s Human Stem Cells and Neurodegeneration Laboratory. “We have shown that it works on three key RNA binding proteins, which is important because it suggests that it may work on other disease phenotypes as well.”

“More research is needed to investigate this question further. We need to see if this could reverse other pathological features of ALS and also, in other models of ALS disease.”

Work to try to understand the mechanisms of ALS disease is ongoing, as shown in a second study by the same group recently published in Brain. Scientists studied transcripts holding introns, sections of RNA that are typically cut from the genetic sequence in a process known as splicing, which also pass from the cell nucleus to the cytoplasm in ALS. By analyzing RNA in diseased motor neurons, they identified more than 100 types of transcripts holding introns in the cytoplasm.

Giulia Tyzack, author and research scientist on the project at the Human Stem Cells and Neurodegeneration Laboratory, says: “We were quite surprised at the number of different transcripts retaining the introns that we found in cells with ALS, which come out of the nucleus and enter the cytoplasm. We didn’t expect to see it to this degree. “

Jacob Neeves, author and scientist from the Human Stem Cells and Neurodegeneration Laboratory, adds: “To imagine what is going on here, we can consider watching a movie in the theater. Typically, we don’t expect to see commercials throughout the film, but, if something goes wrong, those commercials can start popping up at weird and unexpected times. These retained introns look a bit like those anomalous ad breaks. “

Scientists suggest that the collection of transcripts holding introns in the cytoplasm could be a factor that attracts RNA-binding proteins to move through the cytoplasm, although more research is needed to confirm this.

Rickie Patani, senior author, group leader of the Human Stem Cells and Neurodegeneration Laboratory at Crick, professor at the Queen Square Institute of Neurology at UCL, and consultant neurologist at the National Hospital for Neurology and Neurosurgery, says: “Together, our two articles show how laboratory science improves our understanding of such a complex and devastating disease and reassures us that the development of effective treatments will be possible in the future. “

* About 90% of ALS cases are sporadic and 10% are familial, meaning there is a family history of the disease. PCV mutations occur in about 1 to 2% of familial cases.