Monday 21 May 2012
New research brings us closer to understanding the cause of spinal muscular atrophy
Researchers in the US have uncovered further clues about why having low levels of the survival motor neuron (SMN) protein causes the symptoms seen in spinal muscular atrophy (SMA). They found that SMN controls the levels of a protein called plastin 3 (Pls3) so that it is present at a much lower level than normal in SMA. Following a series of experiments they discovered that the lack of pls3 is likely to be contributing to the symptoms of SMA. This is early stage research in an animal model and so further work will need to be done to fully understand if Pls3 has potential as a therapeutic target.
It has been known for some years that SMA is caused by a fault in the survival motor neuron (SMN) gene. This fault leads to a lack of the SMN protein with the result that the nerves controlling the muscles - motor nerves - break down leading to the symptoms seen in SMA. What has been less well understood, however, is why the lack of SMN protein should lead to the break down of motor nerves.
Studies previously carried out in siblings affected by SMA had shown that carrying the same mutation did not always mean they would have the same severity of symptoms. Researchers demonstrated that the cells taken from the less affected siblings had higher levels of a protein called plastin 3 (Pls3). Professor Christine Beattie at Ohio State University, USA worked with colleagues to investigate this further and try to determine what role Pls3 might play in SMA.
The team used a zebrafish model of SMA and showed that these fish had lower than normal levels of Pls3. When they introduced SMN protein back into the fish, the amount of Pls3 protein was also increased to normal. This suggested to the researchers that the amount SMN protein was directly influencing the amount of Pls3 that was present in the zebrafish.
The team then investigated whether the lack of Pls3 was responsible for some of the damaging effects seen in SMA. They were able to introduce small amounts of the Pls3 protein back into the SMA zebrafish. They found that the small increase in Pls3 did not increase the lifespan of the fish, which tend to die very early on, but did have a positive effect on their movement. The SMA zebrafish performed swims and turns far less frequently than the healthy fish. Fish with small amounts of Pls3 tended to swim and turn almost as much as the healthy fish.
When the researchers examined the motor nerves of the fish, they found that the SMA zebrafish had abnormalities in specialised structures where the motor nerve and the muscle meet, called the neuromuscular junction. The fish with small amounts of Pls3 protein added back had far fewer abnormalities.
This research has highlighted one of the ways a lack of the SMN protein acts to damage motor nerves and cause symptoms of SMA. They demonstrated that a lack of SMN affects the amount of Pls3 protein and this in turn can cause problems with the neuromuscular junction (a specialised structure that is affected in SMA), affecting movement.
This is an important piece of research that has contributed to our understanding of exactly what is happening to the motor nerves in SMA. Understanding which proteins, other than SMN, are critical for the function and survival of motor nerves will help researchers to find therapeutic targets and in time develop more effective therapies.
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