Arbour D, Tremblay E, Martineau É, Julien JP, Robitaille R.
Early and persistent abnormal decoding by glial cells at the neuromuscular junction in an ALS model.
J Neurosci. 2015 Jan 14;35(2):688-706.
PubMed.
This is a very interesting paper from the laboratory of one of the foremost experts on interactions between perisynaptic Schwann cells and neurotransmission at the neuromuscular junction. This is the latest in a series of important studies showing the involvement of glial cells in ALS. ALS, like most neurodegenerative diseases, was once believed to be a strictly neuronal disorder, but today we know that all types of glial cells, astrocytes, oligodendrocytes, Schwann cells, microglia, and now perisynaptic (terminal) Schwann cells are involved.
This is the first study I know to examine the involvement of perisynaptic Schwann cells in ALS. These cells surround the neuromuscular junction much like astrocytes surround synapses in the brain and spinal cord, and they seem to have many of the same functions. Perisynaptic Schwann cells modulate the strength of neurotransmission with muscle fibers, and they are especially important in remodeling the neuromuscular junction and in repairing it after injury. It makes good sense that these cells would be involved in ALS and other neuromuscular disorders.
These findings open a new avenue of research for developing new treatments for ALS that target these unusual and important glial cells.
This paper by Arbour et al. from the Robitaille lab reports for the first time that glial cells called perisynaptic Schwann cells (PSCs, aka terminal Schwann cells) at the neuromuscular junction (NMJ) show abnormal properties at the presymptomatic and pre-onset stages in a slowly progressive mouse model (SOD1G37R) of amyotrophic lateral sclerosis (ALS). It is thought that NMJ dysfunction contributes to the pathogenesis of ALS. Given that PSCs are essential to synaptic maintenance and repair at the NMJ, it is critical to examine whether PSC dysfunction may contribute to NMJ dysfunction in this disease. This carefully executed study is very important as it further demonstrates the key role of PSCs in synaptic modulation, maintenance, and repairs at the NMJ, not only in health but also in disease. This study also provides a novel concept of ALS disease mechanisms involving peripheral glial cells.
This paper also raises a number of interesting questions for future investigation. For example, what triggers the enhanced intracellular Ca2+ activation in PSCs and the increased transmitter release seen in these mutant mice? Whether and how does the Ca2+ enhancement play a direct role in NMJ dysfunction in ALS? What happens to PSCs and synaptic strength at later symptomatic stages? Do the same changes occur in other ALS mouse models, such as SOD1G93A, which has a relatively earlier disease onset and is thought to involve dying back of motor nerve terminal at the NMJ? Could activation of G protein pathways in mutant PSCs modulate transmitter release in ALS mice, in a way similar to their previous findings at the normal NMJ? And how can the inadequate activation of muscarinic acetylcholine receptors seen in mutant PSCs be corrected, and could such correction could be used for potential ALS therapy?
Further studies on these questions and the mechanisms of the alterations of the intrinsic PSC properties and synaptic strength would provide a better understanding of NMJ dysfunction in ALS and may lead to a potential therapy by targeting these Schwann cells.
Comments
NIH/NICHD
This is a very interesting paper from the laboratory of one of the foremost experts on interactions between perisynaptic Schwann cells and neurotransmission at the neuromuscular junction. This is the latest in a series of important studies showing the involvement of glial cells in ALS. ALS, like most neurodegenerative diseases, was once believed to be a strictly neuronal disorder, but today we know that all types of glial cells, astrocytes, oligodendrocytes, Schwann cells, microglia, and now perisynaptic (terminal) Schwann cells are involved.
This is the first study I know to examine the involvement of perisynaptic Schwann cells in ALS. These cells surround the neuromuscular junction much like astrocytes surround synapses in the brain and spinal cord, and they seem to have many of the same functions. Perisynaptic Schwann cells modulate the strength of neurotransmission with muscle fibers, and they are especially important in remodeling the neuromuscular junction and in repairing it after injury. It makes good sense that these cells would be involved in ALS and other neuromuscular disorders.
These findings open a new avenue of research for developing new treatments for ALS that target these unusual and important glial cells.
University of Southern California
This paper by Arbour et al. from the Robitaille lab reports for the first time that glial cells called perisynaptic Schwann cells (PSCs, aka terminal Schwann cells) at the neuromuscular junction (NMJ) show abnormal properties at the presymptomatic and pre-onset stages in a slowly progressive mouse model (SOD1G37R) of amyotrophic lateral sclerosis (ALS). It is thought that NMJ dysfunction contributes to the pathogenesis of ALS. Given that PSCs are essential to synaptic maintenance and repair at the NMJ, it is critical to examine whether PSC dysfunction may contribute to NMJ dysfunction in this disease. This carefully executed study is very important as it further demonstrates the key role of PSCs in synaptic modulation, maintenance, and repairs at the NMJ, not only in health but also in disease. This study also provides a novel concept of ALS disease mechanisms involving peripheral glial cells.
This paper also raises a number of interesting questions for future investigation. For example, what triggers the enhanced intracellular Ca2+ activation in PSCs and the increased transmitter release seen in these mutant mice? Whether and how does the Ca2+ enhancement play a direct role in NMJ dysfunction in ALS? What happens to PSCs and synaptic strength at later symptomatic stages? Do the same changes occur in other ALS mouse models, such as SOD1G93A, which has a relatively earlier disease onset and is thought to involve dying back of motor nerve terminal at the NMJ? Could activation of G protein pathways in mutant PSCs modulate transmitter release in ALS mice, in a way similar to their previous findings at the normal NMJ? And how can the inadequate activation of muscarinic acetylcholine receptors seen in mutant PSCs be corrected, and could such correction could be used for potential ALS therapy?
Further studies on these questions and the mechanisms of the alterations of the intrinsic PSC properties and synaptic strength would provide a better understanding of NMJ dysfunction in ALS and may lead to a potential therapy by targeting these Schwann cells.
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