Correcting an RNA error improves communication in laboratory neurons
Correcting a faulty RNA-processing step improved communication between human neurons grown in the laboratory. A peer-reviewed study targeted loss of the UNC13A protein after depletion of another protein linked to motor neuron disease. Genetic removal of an abnormal RNA segment and short RNA-binding molecules restored some signalling measures, while reduced synapse density persisted.
Science··Midday
A processing error disrupts neuronal signals
Correcting an RNA-processing error improved communication between human neurons grown in the laboratory. Researchers investigated a potential approach to motor neuron disease using controlled cell experiments. The peer-reviewed study was published on November 11.[1], [2]
The team generated cortical neurons and spinal motor neurons from human stem cells. Depleting TDP-43, a protein involved in RNA processing, allowed a normally excluded segment to enter UNC13A messenger RNA, the molecule carrying instructions for protein production. UNC13A protein subsequently declined. This protein prepares synaptic vesicles for release of chemical signals between neurons. Communication defects preceded extensive cell death.[1]
Two interventions restore some communication
Researchers genetically removed the abnormal 233-nucleotide segment, known as a cryptic exon. This restored approximately 80 percent of one measure of miniature excitatory electrical currents. A second approach used antisense oligonucleotides, short molecules that bind RNA and redirect its processing. Correctly processed UNC13A RNA and protein production increased.[1]
Some measures of synaptic communication and network activity recovered, but reduced synapse density persisted. A trend towards improved release probability at individual synapses missed the conventional statistical significance threshold. Strong RNA correction also did not produce an equally large protein increase under every experimental condition.[1]
Mice show partial correction after three weeks
Mice carrying the relevant human UNC13A gene region received the RNA-binding molecules. Partial correction was detected in spinal-cord RNA after three weeks. The cell cultures had widespread, relatively uniform TDP-43 depletion, unlike the varied pattern in patient tissues. Restoring UNC13A leaves other consequences of TDP-43 loss unresolved. Dose, tissue distribution, long-term safety and clinical benefit in people remain to be determined.[1]
