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.

Collateral Arteriogenesis Involves a Sympathetic Denervation That Is Associated With Abnormal α-Adrenergic Signaling and a Transient Loss of Vascular Tone

“…The basis for this suggestion is the observation that sympathetic-derived norepinephrine increases netrin synthesis by macrophages in the context of pulmonary fibrosis ( 69 ). It is unclear if vascular smooth muscle cells respond similarly to norepinephrine, but it would not be surprising for a post-synaptic cell to release neurotrophic factors, as occurs at the skeletal myofiber neuromuscular junction ( 70 ). Interestingly, vascular tone is also lost following nerve crush injury and muscle injury, and is only restored with neuronal regeneration ( 71 ) or muscle regeneration ( 72 ), respectively.…”

Sarcopenia: What Is the Origin of This Aging-Induced Disorder?

“…While awaiting progress in this research, it is encouraging that exercise, i.e., frequent use of the MUs, seems to slow down the aging of the connectivity between MNs and myofibers (Love et al, 2003;Soendenbroe et al, 2020). One contributing factor may be the higher levels of neurotrophic factors expressed in exercised over sedentary aged skeletal muscles (Mrówczyński, 2019;Stanga et al, 2020).…”

“…Conversely, the target muscle produces trophic factors (e.g., CNTF, GDNF, NGF, BDNF, and more, reviewed in Kawabuchi et al, 2011;Mrówczyński, 2019;Stanga et al, 2020) that are taken up and retrogradely transported to the MN cell body. These neurotrophins are non-redundant for MN survival during development (Hollyday and Hamburger, 1976) but are continuously expressed throughout life and, as suggested by experimental data, may then serve different functions such as potentiation of transmission and frequency of mEPPs (Gaydukov et al, 2019) (BDNF), maintenance and re-innervation (Stanga et al, 2020) (GDNF), and MN maintenance (BDNF, GDNF; idem). Assessment in aged MNs (and sensory neurons) of the expression of target-derived neurotrophic factor receptors of the NGF family and the expression level of these neurotrophic factors in the target tissue points toward decreased trophic support in old age (Edström et al, 2007).…”

Emerging Potential of Exosomal Non-coding RNA in Parkinson’s Disease: A Review

“…NMJ are usually protected by Schwann cells (SCs) and also represents the site of two-way chemical interaction between nerves and muscles. Interestingly, signals from muscles play an integral role in synapse formation, stability, maintenance, and function ( Stanga et al, 2021 ). MotomiRs are defined as miRNAs essential for the development, maintenance, regeneration and survival of motor neurons ( Hawley et al, 2017 ).…”