The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

Abstract

Brain-derived neurotrophic factor (BDNF) promotes neuron survival in adulthood in the central nervous system. In the peripheral nervous system, BDNF is a contraction-inducible protein that, through its binding to tropomyosin-related kinase B receptor (TrkB), contributes to the retrograde neuroprotective control done by muscles, which is necessary for motor neuron function. BDNF/TrkB triggers downstream presynaptic pathways, involving protein kinase C, essential for synaptic function and maintenance. Undeniably, this reciprocally regulated system exemplifies the tight communication between nerve terminals and myocytes to promote synaptic function and reveals a new view about the complementary and essential role of pre and postsynaptic interplay in keeping the synapse healthy and strong. This signaling at the neuromuscular junction (NMJ) could establish new intervention targets across neuromuscular diseases characterized by deficits in presynaptic activity and muscle contractility and by the interruption of the connection between nervous and muscular tissues, such as amyotrophic lateral sclerosis (ALS). Indeed, exercise and other therapies that modulate kinases are effective at delaying ALS progression, preserving NMJs and maintaining motor function to increase the life quality of patients. Altogether, we review synaptic activity modulation of the BDNF/TrkB/PKC signaling to sustain NMJ function, its and other kinases’ disturbances in ALS and physical and molecular mechanisms to delay disease progression.

P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis

“…Of note is the fact that these growth factors also contribute to maintain MNs in good health. This is the case for VEGF (Wang et al, 2016), BDNF (Lanuza et al, 2019), and GDNF (Thomsen et al, 2018).…”

Delayed increase of acetylcholine quantal size induced by the activity‐dependent release of endogenous CGRP but not ATP in neuromuscular junctions

“…One of such factors could be the absence of contractile activity, which can disrupt muscular feedback control of neurotrophin release from motor nerve terminals (Kim at al., 2019). The role of contractile activity as a trigger of short‐term retrograde signaling that controls synaptic formation and maintenance of synaptic activity remains poorly studied (Lanuza et al., 2019). But growing bulk of evidence demonstrates the acute contraction‐induced secretion of myokines (such as BDNF, ATP, H 2 S etc.)…”

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

“…Among the various neurodegenerative diseases, ALS is the most common neuromuscular disorder that leads to lethal respiratory paralysis within 3-5 years of diagnosis [73]. Usually it occurs after 50 years of age, has an incidence of around five people per 100,000 worldwide, and is more frequent in men [74]. ALS can be classified as either sporadic or familial form, with the majority of cases among the population being sporadic.…”