Blocking small molecule improves motor symptoms in SMA mice
Researchers say RNA molecule plays role in motor neuron diseases
Blocking a small RNA molecule called miR-140-3b can improve motor function in a mouse model of spinal muscular atrophy (SMA), a study suggested.
Reducing miR-140-3b activity increased the levels of KIF5A, a protein involved in the transport of mitochondria (cellular powerhouses) inside nerve fibers.
“We believe that KIF5A has a central role in [motor neuron diseases] as therapeutic and diagnostic [tool], and that developing a strategy able to prevent KIF5A downregulation [low levels] could be beneficial not only in SMA but also in other neurodegenerative diseases,” the researchers wrote. Motor neurons are specialized nerve cells that control movement.
The study, “MiR-140-3p regulates axonal motor protein KIF5A and contributes to axonal transport degeneration in SMA,” was published in Cell Death Discovery.
The progressive loss of motor neurons leads to SMA symptoms such as muscle weakness. SMA is caused mainly by mutations in the SMN1 gene, which normally provides instructions for producing the SMN protein, which is key for motor neuron survival health.
Molecule transport and motor neurons
Although “the molecular pathway involved in selective [motor neuron] degeneration has not been yet elucidated,” some studies suggest that a disruption in axonal transport — the transport of molecules and cellular structures in nerve fibers — is common in diseases affecting motor neurons, the researchers wrote.
Mutations in the KIF5A gene, which encodes a protein involved in axonal transport in the spinal cord, have been associated with motor neuron degeneration and dysfunction of mitochondria. Impairments of mitochondrial structure and transport have been associated with SMA.
Researchers in Italy used a mouse model to investigate the role of KIF5A in SMA. SMA mice are smaller at birth than healthy mice and have a lifespan of about 13 days, with detectable motor impairments a few days after birth. The researchers analyzed changes in KIF5A levels at five days (early symptomatic) and 11 days (late symptomatic).
They found that the levels of KIF5A were 50% lower in the spinal cords of mice with SMA than in controls in both early and later stages of the disease. However, there were no differences in the activity of the Kif5A gene (the mouse form of KIF5A).
The scientists developed a microRNA-based strategy to prevent KIF5A reduction. MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression by binding to messenger RNA, a transient molecule that serves as a template for protein production.
Results showed that miR-140-3p levels were increased in the spinal cords of SMA mice, and that KIF5A levels were significantly lower both in early and late phases of the disease. Further experiments in cells confirmed that the Kif5A gene is a target for miR-140-3 and that the miRNA molecule can modulate this gene’s activity.
When a molecule blocking miR140-3p’s function was given to SMA mice via fluid-filled cavities in the brain, their motor function — including motor coordination — improved. However, there were no effects on lifespan.
The researchers said the results “indicated KIF5A as a distinctive mechanism of [motor neuron diseases] progression.”
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