Scientists at the Francis Crick Institute and UCL have studied how proteins accumulate in the wrong parts of brain cells in motor neurone disease, and have demonstrated how it might be possible, in some cases, to reverse this.
Amyotrophic lateral sclerosis (ALS), more commonly known as motor neurone disease, is a progressive fatal disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, with patients become increasingly paralysed and losing the ability to speak, eat and breathe.
A common occurrence, in 97% of ALS cases, is the abnormal accumulation of proteins involved in the regulation of RNA, called RNA binding proteins, from a motor neuron’s nucleus into the surrounding cytoplasm.
In a new study, published in Brain Communications today (6 August), the researchers used motor neurons grown in the lab from skin cells donated by patients with ALS and showed it is possible to reverse the incorrect localisation of three RNA 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 location of these proteins can be caused when the VCP enzyme is mutated, which has been shown 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 which is currently being tested in phase II cancer trials and also blocks the activity of VCP.
“Demonstrating proof-of-concept for how a chemical can reverse one of the key hallmarks of ALS is incredibly exciting,” says Jasmine Harley, author and postdoctoral researcher in the Human Stem Cells and Neurodegeneration Laboratory at the Crick. “We showed this worked on three key RNA binding proteins, which is important as it suggests it could work on other disease phenotypes too.”