Scientists say they have improved our understanding of how motor neurons respond to motor neuron disease, which could help researchers identify new treatment options. The Wright State University study (“The Vulnerability of Spinal Motoneurons and Soma Size Plasticity in a Mouse Model of Amyotrophic Lateral Sclerosis”), published in the Journal of Physiology, involved identifying and measuring size changes of motor neuron types in a mouse model of familial amyotropic lateral sclerosis (ALS).
The motor neurons were examined at every key stage of the disease to observe when and where these changes begin, and how they progress through the entirety of the disease. Specific antibodies were used as markers to bind to the structure of motor neurons so that they could be easily viewed under high-power microscopes, and a computer program performed the three-dimensional measurement of the size and shape of a motor neuron's cell body.
“Alpha-motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury, and disease. This study examined whether alpha-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and 3D-morphometric analysis of motoneuron size and measures of cell density at four key disease stages: Neonatal, P10 – with earliest known disease changes; young adult, P30 – presymptomatic with early motoneuron death; symptom onset, P90 – with death of 70–80% of motoneurons; and end-stage, P120+ – with full paralysis of hindlimbs. We additionally examined differences in lumbar vs. sacral vs. cervical motoneurons; in motoneurons from male vs. female mice; and in fast vs. slow motoneurons,” write the investigators.
“We present the first evidence of plastic changes in the soma size of spinal α-motoneurons occurring throughout different stages of ALS with profound effects on motoneuron excitability. Somatic changes are time-dependent and are characterized by early-stage enlargement (P10 and P30); no change around symptom onset; and shrinkage at end-stage. A key finding in the study indicates that disease-vulnerable motoneurons exhibit increased soma sizes (P10 and P30). This pattern was confirmed across spinal cord regions, genders, and motoneuron types. This extends the theory of motoneuron size-based vulnerability in ALS: not only are larger motoneurons more vulnerable to death in ALS, but are also enlarged further in the disease. Such information is valuable for identifying ALS pathogenesis mechanisms.”
Motor neuron disease referred to ALS is associated with the death of motor neurons. It starts with the progressive loss of muscle function, followed by paralysis and ultimately death due to inability to breathe. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease. Most people with ALS die within 3 to 5 years from when symptoms first appear.
Previous studies in animal models of ALS have reported inconsistencies in the changes in the size of motor neurons. This new study is the first to show robust evidence that motor neurons change size over the course of disease progression and that, crucially, different types of neurons experience different changes, according to the researchers.
Specifically, the study shows that motor neuron types that are more vulnerable to the disease, I.e., they die first, increase in size early in the disease, before there are symptoms. Other motor neuron types that are more resistant to the disease (they die last) do not increase their size. These changes in the size of the motor neurons have a significant effect on their function and their fate as the diseases progresses.
The hope is that by understanding more about the mechanisms by which the neurons are changing size, it will be possible to identify and pursue new strategies for slowing or halting motor nerve cell death.
This research suggests motor neurons might alter their characteristics as a response to the disease in an attempt to compensate for loss of function. However, these changes can lead to the neuron's early death. Furthermore, the research supports the idea that the most vulnerable motor neurons undergo unique changes that might impact their ability to survive.
The study was carried out in only one mouse model that was the most aggressive mouse model of ALS. Future work should focus on other mouse models of ALS to determine how relevant these results are likely to translate in human patients, notes Sherif M. Elbasiouny, Ph.D., the lead investigator for this research.
“This research approach could be applicable not only to ALS, but also to other neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases,” he says. This new understanding could help us to identify new therapeutic targets for improving motor neuron survival.”