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.
Highlights
We focus on Glial cell line-Derived Neurotrophic Factor (GDNF) since it is the most closely related to neuromuscular junction (NMJ) because of its high expression in muscles and Schwann cells from development to adulthood; since its contribution in pathological conditions, it has been largely studied and tested in clinical trials for many neurodegenerative disorders [19]
The role of GDNF turns out to be decisive from development to aging passing through adulthood by promoting neuroplasticity and preventing from neurodegenerative disorders
In the case of dementia, where a precise diagnosis is difficult in the early disease phase, researchers are largely studying peripheral biomarkers obtained from accessible peripheral fluids—such as blood—and by non-invasive methods [93,94,95]
Summary
The development of the neuromuscular junctions (NMJs) is a complex chain of events in which many factors are intertwined in an extremely coordinated way. The formation of NMJ requires first the guidance of the motor neuron (MN) axons toward the specific muscles for innervation and, secondly, the stabilization of the contact in order to form a mature NMJ. This process of mature synapse formation is a key element for both the proper development and activity of the entire nervous system (NS). The complex interplay between motor axons, terminal Schwann cells and the muscle fibers of the peripheral nervous system (PNS), is reminiscent of the tripartite synapse in the central nervous system (CNS) where pre- and post-synaptic neurons and astrocytes interact (Figure 1). Since defects in signal transmission between terminal nerve endings and muscle membranes are a common feature of several pathologic conditions, the neuro-muscular interplay represents a valuable model to study how the presynaptic message and the postsynaptic feedback collaborate to build a functional synapse, and how a pathological context can alter it
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