According to a study published in the April 11 issue of The Journal of Neuroscience, researchers have found that an abnormally low level of survival motor neuron protein (SMN), in certain nerve cells, is associated with mobility problems that characterize spinal muscular atrophy (SMA) – a deadly childhood disorder.
SMA is a genetic disorder in which motor neurons do not produce enough SMN. Motor neurons are nerve cells that transmit signals from the spinal cord to muscles. SMA causes progressive muscle degeneration and weakness, and some children with the most severe form of SMA die before two years of age.
Prior studies have established that SMN in motor neurons are genetically linked to SMA, although researchers still have no knowledge about how insufficient SMN causes so much damage.
A study conducted by researchers at Ohio State University found that when SMN is missing in zebrafish (in cells throughout the body and in motor neurons specifically), levels of a protein, called plastin 3, decreased as well.
The researchers genetically altered the zebrafish so that they couldn’t produce SMN, thus severely limiting their movement. However, when plastin 3 was added back to motor neurons, the zebrafish regained most of their swimming abilities. According to these results, the presence of plastin 3 – alone, without SMN, is associated to regaining lost movement.
However, the addition of plastin 3 alone is not a treatment option, as the researchers found that zebrafish without SMN in their cells still eventually died. Although, further defining the role that the protein plays in SMA development, will help increase understanding.
Christine Beattie, lead author of the study and associate professor of neuroscience at Ohio State, explained:
“What all is lost when SMN is lost? That’s something we’re still struggling with.
We think part of the motor neuron defects that are seen in spinal muscular atrophy are caused by this decrease in plastin 3 we get when SMN is lowered.
And when we add plastin 3 back to motor neurons we can rescue defects that are seen when SMN is decreased, suggesting that a decrease in plastin 3 is contributing to some of the disease’s characteristics.”
According to the National Institutes of Health, approximately 1 in 6,000 babies born in the United States have SMA. There are many types of SMA and life expectancy depends on how SMA affects breathing. Although drugs and physical therapy can help treat symptoms, at present, there is no cure.
Beattie, and her team began studying SMA several years ago after comparing the blood of siblings – one without SMA, and one with mild SMA. They discovered that the sibling with SMA had lower levels of plastin 3 than the sibling unaffected by the disorder.
Beattie, an expert in using the zebrafish model to research motor neurons and other aspects of the central nervous system, and her team are using animal studies in order to determine the role of plastin 3 in SMA, and how it is specifically linked to SMN.
The researchers genetically altered the zebrafish so they couldn’t produce the SMN protein and found that plastin 3 levels also decreased. However, when the team decreased plastin 3 first in the fish – SMN was unaffected. This findings demonstrate that plastin 3 decreased only when SMN was reduced first. In addition, they found that SMN production was activated in zebrafish initially lacking SMN, plastin 3 levels were also restored.
Beattie explained:
“All this showed a relationship between SMN and plastin 3. It’s not a random event.”
It takes multiple steps in order for genes to make proteins. The researchers found that decreased SMN influences plastin 3 production at a late point in the process called translation, when amino acids are strung together to form the initial shape of the protein.
According to the team, the lack of SMN creates conditions in which insufficient levels of plastin 3 are produced to complete the protein’s normal functions – in the zebrafish, the reduction was approximately four times.
As a result, the researchers plan to research additional proteins that may rely on SMN for their creation.
Beattie, said:
“This is telling us that maybe SMN is affecting translation of other proteins that could be contributing to spinal muscular atrophy. That hasn’t been shown before.”
The researchers found that reduced plastin 3 affects these cells by destroying axons – branch-like extensions that allow for communication among nerve cells, and also by destabilizing synapses – structures through which those signals pass.
Furthermore, the team analyzed fish behavior connected with protein alterations. In the genetically altered zebrafish that do not produce the SMN protein and have decreased levels of plastin 3, the team re-added small amounts of plastin 3 and found that the fish regained their ability to swim and turn, movements they were unable to make previously.
Beattie, explained:
“We’ve rescued axons, synaptic proteins and behavior all by putting plastin 3 back in motor neurons. That’s very encouraging.”
The study received funding from the National Institutes of Health, the SMA Foundation, an Ohio State Neuroscience Center Core Grant and a National Research Service Award Postdoctoral Fellowship.
Co-authors included Le Hao of Ohio State’s Department of Neuroscience and Marc Wolman and Michael Granato of the University of Pennsylvania.
Written By Grace Rattue