Sara Custer, PhD, and her colleagues at Indiana University have published a new paper, “Altered mRNA Splicing in SMN-Depleted Motor Neuron-Like Cells” in the journal PLOS ONE . The research in this paper was funded by a basic research grant from Cure SMA.

Individuals with SMA don’t produce enough survival motor neuron (SMN) protein, due to a mutation in the SMN1 gene. We know this lack of SMN protein causes motor neurons to shrink and eventually die, but there is still much about SMN protein that we don’t know. One of Cure SMA’s basic research priorities is to expand our knowledge of the SMN protein. Our researchers are investigating what critical functions it performs, and where it is lacking in the body tissues of those with SMA.

Dr. Custer and her team are looking specifically at how SMN levels affect the splicing of mRNA, which is a precursor to DNA. mRNA transcripts in motor neurons may be mis-spliced when SMN levels are low, as they are in SMA. This mis-splicing means that parts of the mRNA may be included when they should not be, or vice versa. When this happens it may cause stress that is particularly harmful to these motor neurons.

Importantly, these mis-spliced transcripts may serve as potential targets for the treatment of SMA or as biomarkers that can help track disease severity.

The team at Indiana University tested this by looking at NSC-34 cells. These are mouse motor neuron-like cells that have a SMA-like phenotype that can be restored to normal by expression of human SMN. One of the mRNA transcripts that was mis-spliced in these cells was Rit1. Interestingly, Rit1 is also mis-spliced in the spinal cord of symptomatic SMA mice.

By adding the corrected Rit1 protein back to these SMN-depleted NSC-34 cells, they were able to correct the SMA-like phenotype observed in these cells. This demonstrates that correcting even a single SMN-dependent splice error has the power to restore aspects of normal neuronal architecture without increasing SMN protein levels.

Additional testing in animal models is needed to determine how this finding might be applied in humans.

The Audrey Lewis Young Investigator Award

In 2015, Dr. Custer was the recipient of the Audrey Lewis Young Investigator Award. Audrey Lewis founded Families of SMA, now Cure SMA, 30 years ago. Audrey recognized early on the importance of attracting new and talented researchers to SMA, with the hope that they would commit their careers to developing a treatment and cure for SMA.

Cure SMA honors Audrey’s legacy with the Audrey Lewis Young Investigator Award, which is periodically given to younger researchers working in the SMA field. The goal is to make a positive impact on the early phase of a talented researcher’s career, enabling them to focus on the SMA field.