Abnormalities in the synapses may trigger spinal muscular atrophy

A study from Columbia University demonstrates that spinal muscular atrophy is partly caused by abnormalities in the synapses that connect sensory neurons and motor neurons. The finding extends our knowledge of this devastating disease.

Spinal muscular atrophy (SMA) is a rare, genetic disorder that affects the control of muscle movement. Mutations in the SMN1, UBA1, DYNC1H1, and VAPB genes have been linked to the disease. Most cases of SMA are caused by a genetic defect in the SMN1 gene. To date, at least 65 mutations in the SMN1 gene have been found to cause spinal muscular atrophy. SMN1 provides instructions for making the SMN protein, which is widely expressed in all animal cells and plays a key role in transcriptional regulation, telomerase regeneration, and cellular trafficking. A lack of SMN protein, most often due to genetic mutations in SMN1, leads to the inefficient assembly of the machinery needed to process pre-mRNA. Motor neurons are vulnerable to SMN deficiency and die prematurely. The loss of motor neurons leads to atrophy of muscles used for controlling movement. (Cusabio offers Recombinant app.)

With this knowledge, scientists have long hypothesized that restoring the diseased neurons may treat the disease. However, this approach did not work well in SMA mouse model, indicating that the disease may also involve other cells.

The new study is built on previous research. Dr George Mentis, who led the new study, previously discovered that abnormalities in the synapses between sensory neurons and spinal motor neurons seem to contribute to SMA development before the death of motor neurons. In this work, Mentis' team demonstrated in SMA mouse model that SMN shortage in sensory neurons changed the synapses that connect them to motor neurons, leading to a reduction in the release of glutamate, a key neurotransmitter involved in neural activation, which in turn decreased the expression of the potassium channel Kv2.1 at the surface of motor neurons. Reduced Kv2.1 expression affects the function of motor neurons and their control on muscles. The researchers noted that “a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments.”

The researchers also found that increasing neuronal activity pharmacologically almost normalized Kv2.1 expression and improved motor function. Based on these results, the researchers believed that abnormalities in sensory synapses contribute to SMA development. Therefore, increasing synaptic activity might be a way to treat SMA.

The study “Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy” appears in Nature Neuroscience.