New perspectives on amyotrophic lateral sclerosis: the role of glial cells at the neuromuscular junction

Abstract

Amyotrophic lateral sclerosis (ALS) is a disease leading to the death of motor neurons (MNs). It is also recognized as a non-cell autonomous disease where glial cells in the CNS are involved in its pathogenesis and progression. However, although denervation of neuromuscular junctions (NMJs) represents an early and major event in ALS, the importance of glial cells at this synapse receives little attention. An interesting possibility is that altered relationships between glial cells and MNs in the spinal cord in ALS may also take place at the NMJ. Perisynaptic Schwann cells (PSCs), which are glial cells at the NMJ, show great morphological and functional adaptability to ensure NMJ stability, maintenance and repair. More specifically, PSCs change their properties according to the state of innervation. Hence, abnormal changes or lack of changes can have detrimental effects on NMJs in ALS. This review will provide an overview of known and hypothesized interactions between MN nerve terminals and PSCs at NMJs during development, aging and ALS-induced denervation. These neuron-PSC interactions may be crucial to the understanding of how degenerative changes begin and progress at NMJs in ALS, and represent a novel therapeutic target.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…Because Schwann cell dissociation from NMJ is mainly caused by the axon retraction from motor plates (17,68), our results further suggest the halt of distal motor axon degeneration following treatment with masitinib. A potential important finding for ALS pathogenesis is the almost complete disappearance we found of capillaries in EDL muscle areas devoid of NMJ innervation.…”

“…Perisynaptic Schwann cells are glial cells at the NMJs that ensure the synapse stability, maintenance, and repair during damage or denervation (41). Perisynaptic Schwann cells respond to ALS-induced denervation with profound morphological and phenotypic changes (17), retracting processes from the NMJs while extending processes to other endplate areas (42). Therefore, we examined whether downregulation of mast cells in masitinib-treated rats was associated to preservation of perisynaptic Schwann cells in the EDL muscle, as analyzed by confocal microscopy followed by 3-D reconstructions.…”

“…functional Schwann cells, and defective stabilization of NMJs have been proposed as potential pathogenic defects triggering the "dying back" of motor axons (15)(16)(17). Finally, evidence for such dying back motor neuropathy has also been found in some clinical forms of ALS (2,16), suggesting a key pathogenic event that could be targeted by therapeutic interventions.…”

Smoke‐induced neuromuscular junction degeneration precedes the fibre type shift and atrophy in chronic obstructive pulmonary disease

“…; Arbour et al . ). For example, in the context of muscle‐specific retrograde signalling to the neuromuscular junction, recent studies have shown that muscle‐specific disturbances in (1) autophagy (Carnio et al .…”

“…The neuromuscular junction is the interface between the motor neuron and muscle fibre and is a point of vulnerability in various neuromuscular diseases (Comley et al 2016;Boido & Vercelli, 2016) and normal ageing (Hepple & Rice, 2016). Importantly, previous studies have established that factors intrinsic to motor neurons, perisynaptic Schwann cells and muscle fibres may each contribute to neuromuscular junction degeneration in different contexts (Lieberman et al 2014;Sakellariou et al 2014;Arbour et al 2017). For example, in the context of muscle-specific retrograde signalling to the neuromuscular junction, recent studies have shown that muscle-specific disturbances in (1) autophagy (Carnio et al 2014), (2) the G93A mutation of superoxide dismutase 1 (SOD1) seen in a familial form of ALS (Dobrowolny et al 2018) and (3) FGFBP1 secretion (Taetzsch et al 2017) can each cause neuromuscular junction degeneration.…”