Specific Protein, Sema3A, Affects Survival of Motor Neurons in ALS, Early Research Shows

Researchers homed in on how a particular protein, called semaphorin 3A (Sema3A), affects the survival of motor neurons in both the brain and spinal cord in models of amyotrophic lateral sclerosis (ALS).

Their study, “ALS-related human cortical and motor neurons survival is differentially affected by Sema3A,” appeared in the journal Cell Death & Disease.

Despite extensive research demonstrating a growing number of mutated genes are associated with the disease, the molecular basis of ALS is still not well understood.

ALS affects motor neurons both in the cerebral cortex (cortical part) of the brain and the spinal cord. In an effort to decipher the molecular mechanisms behind ALS, scientists have been studying factors that influence motor neuron development.

One of these factors is semaphorin 3A (Sema3A), a guidance molecule that belongs to a protein family that regulates the growth of the long fibers that extend from neurons, called axons, including those of spinal motor neurons. Motor neuron axons are responsible for transmitting signals as electric impulses to muscle cells, causing muscles to contract or relax.

Studies in mice suggest that Sema3A contributes to the survival of spinal motor neurons. Regarding its association with ALS, research showed that the levels of both Sema3A and its receptor — neuropilin 1 (NRP1) — are increased in a mouse model of the disease. Furthermore, blocking NRP1 with an antibody given the mice at 40 days of age delayed and even temporarily reversed the motor decline, while prolonging their life span.

Altered levels of Sema3A were also described in post-mortem samples from ALS patients. Higher than usual Sema3A levels were found in their motor cortex, and lower Sema3A  levels in those of the spinal cord, though the difference was not statistically significant. Understanding the role of Sema3A in the survival of human brain and spinal motor neurons clearly requires more studies.

The research team conducted a series of experiments to assess the response of human cortical and spinal motor neurons to Sema3A.

Sema3A was seen to improve the survival of spinal cord motor neurons. The researchers attributed this effect to an increase in neuronal survival. This hypothesis was later confirmed by monitoring neurons with microscopy. Subsequent analysis indicated that Sema3A primarily impacts the survival of more mature motor neurons, the researchers said.

In contrast, Sema3A worked against the survival of cortical neurons. Changes in both spinal motor and cerebral cortex neurons were the blocked with an anti-NRP1 antibody, demonstrating that the effect seen were specific to Sema3A.

“Our results demonstrate that, similar to mouse neurons, Sema3A functions as a death signal for human cortical neurons and as a survival factor for spinal [motor neurons],” the researchers wrote.

“Taken together with the increase of Sema3A in the motor cortex of postmortem ALS patients and the tendency for lower expression in the spinal cord of postmortem ALS patients, our results imply that Sema3A functionally contribute to the pathology of ALS both at the level of the motor cortex and the level of the spinal cord,” they added.