How to Build and to Protect the Neuromuscular Junction: The Role of the Glial Cell Line-Derived Neurotrophic Factor

Abstract

The neuromuscular junction (NMJ) is at the crossroad between the nervous system (NS) and the muscle. Following neurotransmitter release from the motor neurons (MNs), muscle contraction occurs and movement is generated. Besides eliciting muscle contraction, the NMJ represents a site of chemical bidirectional interplay between nerve and muscle with the active participation of Schwann cells. Indeed, signals originating from the muscle play an important role in synapse formation, stabilization, maintenance and function, both in development and adulthood. We focus here on the contribution of the Glial cell line-Derived Neurotrophic Factor (GDNF) to these processes and to its potential role in the protection of the NMJ during neurodegeneration. Historically related to the maintenance and survival of dopaminergic neurons of the substantia nigra, GDNF also plays a fundamental role in the peripheral NS (PNS). At this level, it promotes muscle trophism and it participates to the functionality of synapses. Moreover, compared to the other neurotrophic factors, GDNF shows unique peculiarities, which make its contribution essential in neurodegenerative disorders. While describing the known structural and functional changes occurring at the NMJ during neurodegeneration, we highlight the role of GDNF in the NMJ-muscle cross-talk and we review its therapeutic potential in counteracting the degenerative process occurring in the PNS in progressive and severe diseases such as Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). We also describe functional 3D neuromuscular co-culture systems that have been recently developed as a model for studying both NMJ formation in vitro and its involvement in neuromuscular disorders.

Keywords: 3D neuromuscular model; AD; ALS; GDNF; SMA; motor neuron diseases; neurodegenerative diseases; neuromuscular junctions; neurotrophic factors.

Figure 1

The central vs. the peripheral tripartite synapse. The NMJ is at the crossroad between the NS and the muscle, representing their cross-talk point. Central and peripheral synapses share a similar morphological feature: the tripartite synapse. Indeed, in the CNS the tripartite synapse is composed by a presynaptic axon (A), a postsynaptic dendrite (B) and by astrocytes (C). In the PNS, there is a comparable structure and the tripartite communication is between the axon terminal of the MN (A′), the muscle fiber (B′) and the terminal Schwann cells (C′). The macromolecules involved at the nerve–muscle interplay are represented in the zoomed section. Created with BioRender software.

Figure 2

Peripheral dysfunctions in SMA. SMA is characterized by progressive MN death, impaired innervation and muscular atrophy, contributing to NMJ destabilization. Among the known pathogenic mechanisms, mitochondrial alterations represent an early event. As shown in the Electron Microscopy images from spinal cord samples of the SMNΔ7 mice (postnatal day 10), compared to the control (CTRL), SMA mitochondria are clearly altered, dilated and fragmented. N = nucleus; m = mitochondria. Created with BioRender software.