Ocular Motor Nerve Cells Adapt to Loss of SMN Protein in Protective Ways, Study Finds

Researchers in a mouse model of spinal muscular atrophy (SMA) have discovered why certain nerve cells, called ocular motor neurons, are able to resist the damage and degeneration linked to the disease.

Their study, “LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy,” was recently made available by bioRxiv.

SMA is caused by mutations in the SMN1 gene, considerably lowering the amount of the SMN protein produced. SMN, present in all cells, is necessary for the survival of motor nerve cells, or motor neurons, which are progressively lost during disease progression.

In SMA, spinal motor neurons — nerve cells in the spinal cord that control skeletal muscle movements, including the arms and legs — are those mainly affected. Their loss leads to weakness and atrophy of skeletal muscles, affecting voluntary movement.

For unknown reasons, certain types of cranial motor neurons in the brainstem — the region at the base of the brain that connects with the spinal cord — show partial or even no damage in SMA patients.

Among cranial motor neurons, those that control the muscles of the tongue are affected to some extent, and those controlling the eyes — called ocular motor neurons — are resistant to SMA-associated degeneration.

Understanding why ocular motor neurons are spared in SMA may help in developing new treatment approaches, particularly gene therapies, and in preventing progressive motor neuron loss.

Using a mouse model of SMA, researchers conducted a comprehensive analysis of vulnerable and resistant nerve cell groups at several stages of the disease.

They used an approach called LCM-seq that couples laser microdissection of cells from frozen tissues with analysis of gene expression (the process by which information in a gene is synthesized to create a working product, like a protein).

Dissected nerve cells came from the spinal cord and brainstem regions of healthy mice and  mice at different stages of SMA: a pre-symptomatic stage, an early symptomatic stage (damage restricted to some regions of the spinal cord), and a symptomatic stage (clear motor dysfunction and extensive loss of spinal motor nerve cells).

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Researchers found 251 genes highly associated with SMA, from which 113 genes (45%) were differentially expressed to a significant degree in both disease-vulnerable and -resistant types of motor neurons from the SMA mice.

In response to low SMN protein levels, all motor nerve cells showed significant expression of genes associated with stress-responses and cell death, independent of their vulnerability to SMA.

To understand how — despite activated cell death signals — ocular motor neurons were able to resist damage due to SMA, the researchers compared the expression patterns of these resistant ocular motor neurons with those of vulnerable spinal motor neurons.

They found signs of nerve cell dysfunction upon loss of SMN in the vulnerable neurons. But the resistant neurons rapidly and selectively adapted: they increased the expression of genes that are associated with cell survival, with protection from oxidative stress and cell death, and with regeneration and/or maintenance of communication signals between nerve cells and muscle cells.

“We show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience,” the researchers wrote.

They also noted these cell-specific mechanisms “present compelling targets for future gene therapy studies aimed towards preserving vulnerable motor neurons,” in the context of motor nerve cell diseases.