Researchers Find Potential Target For Spinal Muscular Atrophy

Researchers have identified Neurexin2 as a novel target to treat neurodegeneration in spinal muscular atrophy patients.

AsianScientist (Dec. 20, 2013) – Researchers have found a possible new route for treatment of spinal muscular atrophy (SMA), a disease that is the most common genetic cause of infant death and that also affects young adults.

The study, led by Associate Professor Christoph Winkler of the Department of Biological Sciences at the National University of Singapore (NUS) and Dr. Kelvin See, research fellow at the Genome Institute of Singapore (GIS), was published in the journal Human Molecular Genetics.

SMA is a genetic disease that attacks a distinct type of nerve cells called motor neurons in the spinal cord. The disease is caused by a defect in the SMN gene, a widely used gene that is responsible for normal motor functions in the body.

Using global genome analysis, the team found that deficiency in the SMN gene impairs the function of the Neurexin2 gene. This in turn limits the neurotransmitter release required for the normal function of nerve cells. The degeneration of motor neurons in the spinal cord causes SMA.

In laboratory experiments, the researchers showed when SMN activity in zebrafish was reduced to levels found in human SMA patients, Neurexin2 function was impaired. This novel disease mechanism was also discovered in other in vivo models, suggesting that it is applicable to mammals and possibly human patients.

When the scientists measured the activity of nerve cells in zebrafish using laser imaging, they found that nerve cells deficient for Neurexin2 or SMN could not be activated to the same level as healthy nerve cells. This impairment consequently led to the reduction of muscular activity. Interestingly, preliminary data showed that a restoration of Neurexin2 activity could partially recover neuron function in SMN deficient zebrafish.

“These findings significantly advance our understanding of how the loss of SMN leads to neurodegeneration. A better understanding of these mechanisms will lead to novel therapeutic strategies that could aim at restoring and maintaining functions in deficient nerve cells of SMA patients,” said Professor Winkler.

Moving forward, the team of scientists will conduct further research to determine if Neurexin2 is an exclusive mediator of SMN induced defects and hence can be used as a target for future drug designs. As there is currently no known cure for SMA, the new discovery gives a strong boost to the fight against the disease.

The article can be found at: See K et al. (2013) SMN deficiency alters Nrxn2 expression and splicing in zebrafish and mouse models of spinal muscular atrophy.

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Source: National University of Singapore; Photo: Thomas Huy Photography/Flickr/CC.
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