Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a highly debilitating disease caused by progressive degeneration of motorneurons (MNs). Due to the wide variety of genes and mutations identified in ALS, a highly varied etiology could ultimately converge to produce similar clinical symptoms. A major hypothesis in ALS research is the “distal axonopathy” with pathological changes occurring at the neuromuscular junction (NMJ), at very early stages of the disease, prior to MNs degeneration and onset of clinical symptoms. The NMJ is a highly specialized cholinergic synapse, allowing signaling between muscle and nerve necessary for skeletal muscle function. This nerve-muscle contact is characterized by the clustering of the collagen-tailed form of acetylcholinesterase (ColQ-AChE), together with other components of the extracellular matrix (ECM) and specific key molecules in the NMJ formation. Interestingly, in addition to their cholinergic role AChE is thought to play several “non-classical” roles that do not require catalytic function, most prominent among these is the facilitation of neurite growth, NMJ formation and survival. In all this context, abnormalities of AChE content have been found in plasma of ALS patients, in which AChE changes may reflect the neuromuscular disruption. We review these findings and particularly the evidences of changes of AChE at neuromuscular synapse in the pre-symptomatic stages of ALS.

Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model

“…Neuromuscular junction destruction is an early pathological change in SOD1‐G93A mice . We labeled NMJs on cross section of gastrocnemius muscle using α‐bungarotoxin.…”

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

“…Evidence in ALS patients and murine models expressing ALS‐linked SOD1 mutations indicate that peripheral axons are lost before the death of cell bodies in the central nervous system (CNS; Fischer et al, ; Frey et al, ; Kennel, Finiels, Revah, & Mallet, ). Degeneration of motor axons in ALS has been associated with defective axonal transport, mitochondria function, and/or destabilization of neuromuscular junctions, among others (Arbour, Tremblay, Martineau, Julien, & Robitaille, ; Campanari, Garcia‐Ayllon, Ciura, Saez‐Valero, & Kabashi, ; Kong & Xu, ; Millecamps & Julien, ). The progressive loss of motor axons in ALS results in a Wallerian‐like degeneration characterized by axon fragmentation, the disintegration of the axonal cytoskeleton, myelin degradation, and immune cell infiltration (Chiu et al, ; Fischer & Glass, ), representing a stereotyped response to promote axonal growth and nerve repair.…”

P2X7 activation enhances skeletal muscle metabolism and regeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis

“…It was reported that muscle weakness has an important role in ALS pathology, although it is not clear whether denervation originates from the motor neuron soma, or the muscle . Previous studies have shown that the exclusive expression of mutant SOD1G93A (mSOD1) in the skeletal muscles can lead to denervation of the neuromuscular junctions (NMJs), which lose the ability to regenerate and become atrophic, thus contributing to the symptoms of ALS . Indeed, several mechanisms implicated in the physiological maintenance of skeletal muscle are deregulated in ALS, such as satellite cell (SC) activity, mitochondrial and miRNA biogenesis .…”

“…regenerate and become atrophic, thus contributing to the symptoms of ALS (7). Indeed, several mechanisms implicated in the physiological maintenance of skeletal muscle are deregulated in ALS, such as satellite cell (SC) activity, mitochondrial and miRNA biogenesis (17,18,31,41).…”