Stabilizing Motor Neuron Survival Protein Might Lead to New ALS Treatments, Harvard Researchers Find

A compound that stabilizes a protein crucial for the survival of motor neurons helped cells of amyotrophic lateral sclerosis (ALS) patients survive longer in experiments performed in lab dishes.

The discovery builds on research about a childhood neuromuscular disease — spinal muscular atrophy (SMA) — and may lead to new treatments for both conditions, according to the study, “Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease,” which appeared in the journal Cell Reports.

The survival of motor neuron (SMN) protein is abnormal in children with SMA, who carry mutations in the gene coding for the protein. Although SMN exists in all cells, motor neurons are, for some reason, more vulnerable to the lack of this protein and start dying first.

When researchers at the Harvard Stem Cell Institute (HSCI) studied cells from SMA patients, they were in for another surprise: not only do motor neurons die before other cell types, but individual neurons die at very different rates.

“Clearly, some motor neurons were surviving, so the next question was whether this is random or if there is a molecular explanation,” Lee Rubin, a professor at the Harvard Department of Stem Cell and Regenerative Biology and the study’s senior author, said in a press release.

An analysis revealed that within a single petri dish of motor neurons derived from an SMA patient, some produced up to four times as much SMN protein as their neighbors. The cells with more of the protein were more likely to survive, just as when researchers exposed them to various types of stress.

“The surprise was when we looked in a control culture and also saw differences between the individual neurons,” said Rubin, who is also an HSCI executive committee member.

“It is clear that the SMN protein is necessary for all motor neuron survival, not just motor neurons targeted by ALS or SMA,” added Natalia Rodríguez-Muela, a postdoctoral researcher in Rubin’s lab and lead author of the study.

Equipped with this knowledge, the team went back to search for potential compounds that could increase the amount of SMN in the cells.

They homed in on a factor that belongs to a family of proteins called Cullins. Just as they had suspected, blocking the protein made SMN less likely to degrade, and cell levels of the protein increased. They saw the same effect in human lab-grown neurons and mouse models of ALS and SMA.

“This discovery opens up new lines of drug interrogation,” said Rubin, adding that the discovery points to an “unexplored therapeutic direction that could benefit patients of not one, but two separate diseases.”