ALS Research Could Shed Light on What Drives SMA, Study Reports

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Spinraza and CSF changes

New research on amyotrophic lateral sclerosis (ALS) may shed light on the mechanisms underlying spinal muscular atrophy (SMA), scientists say.

The study, “TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis,” appeared in the journal Brain.

Two RNA binding proteins, TDP-43 and hnRNP A1, are abnormal in certain cases of ALS.  This leads to their accumulation in ALS patients’ movement nerve cells — in cell structures called cytoplasmic inclusions. As the name suggests, RNA binding proteins have the capacity to bind with RNA molecules, limiting their ability to become proteins.

University of Montreal researchers wanted to understand what happened to movement nerve cells when they removed TDP-43 from the cells’ nucleus.

“Our specific focus was on other types of RNA binding proteins that could be interesting players in the disease,”Jade-Emmanuelle Deshaies, a neurosciences research associate at UdeM Hospital Research Center (CRCHUM), said in a press release. “One of these, hnRNP A1, caught our eye. In particular because there was a second form that is rarely mentioned in the literature [studies],” said Deshaies, the lead author of the study.

Depleting nucleus TDP-43 led to changes in the processing, or splicing, of messenger RNA in the cell. Because TDP-43 binds with RNA, and can change how it is spliced, depleting it in the cell nucleus led to alterations to another RNA binding protein, hnRNP A1. This protein can get spliced into two variations, both regulated by TDP-43.

“The data we have show that when TDP-43 is either not there at all, or is just absent from the nucleus, you can change the splicing pattern of hnRNP A1,” said Christine Vande Velde, associate professor of neurosciences at the University of Montreal and study lead author. “The big picture is that there is a much more broad spectrum of RNA metabolism mis-regulation than what was previously thought. And with that, we get more understanding of what’s going wrong, and given this new knowledge, we can potentially develop a therapy that targets this mechanism.”

Changes in hnRNP A1 messenger RNA also resulted in protein aggregation and were toxic to cells. Importantly, hnRNP A1 controls splicing of the SMN gene, the underlying cause of SMA.

Researchers don’t now how the hnRNP A1-triggered SMN splice variation affects the function of the SMN gene. But they noted that Spinraza, a therapy recently approved for SMA, targets the hnRNP A1 protein’s splicing of the gene.

“The drug is nusinersen, sold commercially as Spinraza,” said Vande Velde. “When you give it to babies early enough, you can fix their spinal muscular atrophy. Babies that were not able to roll over, or walk, now can. Babies that would normally die within the first two or three years of life are able to reach the developmental milestones. It’s being reported as a real cure for the most severe forms of the disease.”

Spinraza, developed by Cold Spring Harbor Laboratory and Ionis Pharmaceuticals, derived from the same type of research Vande Velde is performing.

“They did the type of work we’ve been doing, which is to understand how a gene is spliced,” she said.

“It took many years to get to that point, and similarly, our work is just the first cog in the wheel. Whether or not there really is an influence on the expression or the splicing of the very important gene SMN, or other genes important for motor neuron [movement nerve cell] survival, is something we need to evaluate.”