Motor neurodegeneration in amyotrophic lateral sclerosis (ALS) can begin in axons at neuromuscular junctions and later spread to the cell body in the spinal cord, in a phenomenon known as the “dying back” hypothesis. Proteins involved in axonal regeneration may, for this reason, represent a potential therapeutic target in ALS.
A research team from Germany found increased levels of Semaphorin 3A (Sema3A), an axon guidance protein, in ALS patients. Their study, titled “The Axon Guidance Protein Semaphorin 3A Is Increased in the Motor Cortex of Patients With Amyotrophic Lateral Sclerosis,” was published in the Journal of Neuropathology & Experimental Neurology.
Semaphorins are important for axonal regeneration and the maintenance of motor neuron circuits. However, Sema3A can act as an axon repellent and prevent axonal regeneration. In fact, increased Sema3A levels have been described in a mouse model of ALS.
This finding led the authors to investigate the expression of this specific protein in the central nervous tissue of eight ALS patients, compared to six controls with no history of neurological disease. Using real-time polymerase chain reaction and in situ hybridization, they were able to detect Sema3A at the mRNA level in motor neurons. Moreover, immunohistochemistry analysis in motor cortex and spinal cord tissue detected Sema3A at the protein level, especially in the cytoplasm and axons of motor neurons of ALS patients.
Researchers believe that the increase of Sema3A, found through the three different methods, may contribute to axonal degeneration and prevent regeneration in ALS patients. In fact, in animal models of peripheral nervous system (PNS) and central nervous system (CNS) injury, the inhibition of Sem3A has been shown to be beneficial. “Previous studies in models of PNS and CNS injury indicate that our finding of increased Sema3A expression in ALS patients might have therapeutic potential. Treatment of spinal cord-injured rats with the selective Sema3A inhibitor SM-216289 resulted in enhanced regeneration and/or preservation of injured axons,” the authors wrote in their study.
Inhibition of Sema3A might hold a therapeutic potential in ALS. “The present study, for the first time, describes increased Sema3A expression in human ALS motor cortex. Our results suggest that selective inhibition of Sema3A or its downstream pathways might be a promising novel therapeutic approach for the treatment of ALS patients,” the authors concluded.