Spasticity in Amyotrophic Lateral Sclerosis: It all Comes Down to Serotonin

Science

What causes the spasticity observed in patients suffering from amyotrophic lateral sclerosis, a symptom involving painful, debilitating muscle stiffness? A new study has revealed that it is induced by the degeneration of serotonin neurons located in the brain stem, rather than that of the cortex motor neurons as was previously believed. This discovery opens the path for the development of a therapy to relieve this symptom in a variety of illnesses.

Surprisingly, serotonin neurons are involved in spasticity associated with amyotrophic lateral sclerosis (ALS, also known as motor neuron disease). Until now, scientists thought that the cause of this muscle stiffness could only be found in the death of cortex neurons involved in movement. But an Inserm team has shown that this avenue is probably false: While cortex motor neurons undoubtedly play a role, those that are important in spasticity are the serotonin neurons located in the brain stem.

In amyotrophic lateral sclerosis, the neurons involved in controlling movement in the brain (in the motor cortex) gradually degenerate, as do the motor neurons located lower downstream, in the spinal cord, from which they control the muscles that they innervate directly. The death of these various cells causes progressive paralysis, including of the respiratory muscles, leading to death between 3 and 5 years after the onset of the disease. Spasticity is one of the major symptoms of the illness. This is defined as muscle stiffness triggered by strong involuntary contractions. These contractions are violent, painful, and debilitating. Until this new study, the mechanisms that caused this symptom remained enigmatic.

Lack of Spasticity Increases the Speed of ALS Development

5-HT2B, a serotonin receptor produced by neurons labeled green. In red the motoneurons.
5-HT2B, a serotonin receptor produced by neurons labeled green. In red the motoneurons. 5-HT2B has a protective power against ALS or Charcot's disease. © Inserm/El Oussini, Hajer/U118

To learn more, the researchers turned their attention to serotonin neurons. Recent research has shown that these neurons also degenerate in patients suffering from ALS. On top of that, one serotonin receptor (5-HT2B/C) is involved in the inflammatory mechanisms of the disease. These are troubling facts.

The scientists used an ALS mouse model in which the disease is induced by a mutation of the SOD1 gene, with the luxury of being able to restore the activity of this gene in only some cell populations. By using this possibility in the serotonin neurons, and therefore by specifically preventing the degeneration of these cells, they observed a lack of spasticity in the animals. However, this theoretical benefit came with an increase in the speed of paralysis of the mice and the death of the motor neurons. “We were not surprised by this, as spasticity is in fact a compensatory mechanism that allows the muscles to continue contracting, so that they can move despite the death of the motor neurons. Without this phenomenon, the muscles atrophy more quickly and this study confirms that,” explains Luc Dupuis, who is leading the research.

A Therapeutic Avenue for Non-ALS Spasticity Cases

Unfortunately, this means that it is illusory to intend to relieve patients suffering from ALS by blocking spasticity. Nevertheless, the discovery of this mechanism opens a therapeutic avenue for relieving spasticity in other diseases that are not associated with motor neuron degeneration. “This symptom can also be observed in multiple sclerosis and in spinal cord lesions,” Dupuis adds. In this respect, the team has just begun conducting research on animal models with spinal cord lesions. The goal is to block the abnormal mechanisms triggered by serotonin loss and to reduce spasticity. 

Note

*Inserm unit 1118/University of Strasbourg, Central and Peripheral Mechanisms of Neurodegeneration, Medical School, Strasbourg

Source

H. El Oussini et coll. Ann Neurol, online edition of August 30, 2017

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