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Review
. 2019 Aug 13;13:368.
doi: 10.3389/fncel.2019.00368. eCollection 2019.

The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis

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Free PMC article
Review

The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis

Jonu Pradhan et al. Front Cell Neurosci. .
Free PMC article

Abstract

Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A2 a Rs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A2 a Rs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A2 a Rs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A2 a Rs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A2 a Rs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.

Keywords: A2aR; ALS; BDNF; MND; TrkB receptors; motor neurons.

Figures

FIGURE 1
FIGURE 1
Schematic diagrams showing the regulation of glutamatergic synaptic transmission at upper and lower MN synapses in normal and SOD1G93A mice. The arrival of the action potential (step 1), triggers the influx of Ca2+ ions into pre-synaptic terminal (step 2), the rise in intracellular calcium (step 3) in turn triggers the fusion of synaptic vesicles with the pre-synaptic membrane to release glutamate (light purple dots) from the terminal (step 4). Binding of glutamate to its postsynaptic receptors (NMDA, green; and AMPA, magenta; step 5), leads to the influx of Ca2+ ions. During this process, concentration of glutamate within the synaptic cleft is reduced by the uptake of glutamate into Astrocytes (orange star shaped cells) via EAAT2 glutamate transporters (pink; step 6). Within the post-synaptic neuron the influx of Ca2+ via glutamatergic receptors plus voltage gated Ca2+ channels, along with an influx of sodium (Na+) ions lead to the activation of the postsynaptic neuron (step 7). The subsequent lowering of Ca2+ post-synaptic transmission is managed by extrusion of calcium via ATP pumps (PMCA pumps) and Na+/Ca2+ exchanger (NCX), plus calcium uptake into intracellular stores (ER and mitochondria) (Chio et al., 2012). The right panel shows the pathogenesis of glutamate induced excitotoxicity in ALS. Excessive glutamate released in the synaptic cleft triggers increased activation of the post-synaptic glutamate receptors (NMDA and AMPA receptors). This effect is enhanced due to dysfunctional glutamate transporters (EAAT2; step 6, right panel, red dashed arrow), which lengthen the persistence of glutamate within the synaptic cleft (step 7, right panel), which further activates glutamatergic receptors. Impaired Na+/Ca2+ exchanger and ATP pumps in SOD1G93A mice results in enhanced Ca2+ intracellularly (DeJesus-Hernandez et al., 2011; Sirabella et al., 2018). Generation of reactive oxygen species (ROS) causes neuronal membrane peri-oxidation impairing the glutamate transporters (EAAT2). The enhanced activation of these receptors leads to increased Ca2+ overload (step 8, right panel) in the post-synaptic neuron, which in turn leads to mitochondrial dysfunction (step 9, right panel), oxidative stress (step 10, right panel), and generation of reactive oxygen species (ROS) ultimately leading to motor neuron death (step 11, right panel).
FIGURE 2
FIGURE 2
Schematic presentation of BDNF synthesis from translation, intracellular processing through to its secretion. BDNF is synthesized from the BDNF gene in a multi-step process. Intracellularly, the pre-pro BDNF is produced in the endoplasmic reticulum which is then translocated toward the Golgi apparatus, where the pre-sequence is cleaved off to form pro- BDNF. The pro-BDNF is further processed, via the Golgi apparatus, into the trans-Golgi network (TGN) where the pro domain is cleaved off by proteases to form mature BDNF (BDNF). The pro-BDNF is proteolytically cleaved by furin or convertase and is intracellularly secreted as BDNF. Both pro-BDNF and BDNF are preferentially grouped and packaged into secretory dense core-vesicles and secreted extracellularly via exocytosis. The extracellularly secreted pro-BDNF is then processed and catalyzed by proteases such as plasmin and metalloproteinases (MMP2 and MMP9) to form BDNF. As a result, three functionally active isoforms, namely pro-domain, pro-BDNF and BDNF are secreted extracellularly. Adapted from Kowianski et al. (2018).
FIGURE 3
FIGURE 3
Intrinsic intracellular signaling cascades of BDNF-TrkB and TrkB-A2a receptors. BDNF-TrkB activation predominantly initiates MAPK, PI3K, and PLC γ signaling pathways. Activation of the TrkB receptor at its Tyr490 and Tyr515 residue recruits Shc adaptor protein leading to binding of growth factor receptor bound protein 2 (grb2) which binds with GTPase Ras to form a complex and initiate extracellular signal regulated kinase (ERK) activation which in turn activates the mitogen activated protein kinase MAPK/ERK pathway, which results in the activation of CREB transcription factor. Activation of Tyr515 residue also activates the PI3K signaling pathway, incorporating combined actions of Ras and activating the PI3/Akt and MEK/MAPK pathways. Both MAPK and PI3K signaling exert neurotrophic functions of survival, growth and differentiation, via activation transcription factors (CREB and C-myc). Phosphorylation of the TrkB receptor at its Tyr816 residue activates the phospholipase C γ (PLC γ) pathway, generating inositol-1, 4, 5-triphosphate (IP3) and diacylglycerol (DAG). The PLCγ/IP3 pathway results in calcium release from intracellular stores, in turn activating Ca2+/CaMKII. DAG activates PKC, leading to synaptic plasticity. pro-BDNF/p75 initiates JNK signaling (Reichardt, 2006; Anastasia et al., 2013; Kowianski et al., 2018) triggering neuronal apoptosis (Teng et al., 2005), and the NF-κB signaling cascade regulation of neuronal growth cone development and navigation, and neuronal survival. Like BDNF, neuronal activity promotes release of adenosine which binds to A2aRs to activate adenylyl cyclase leading to production of cAMP further activating PKA downstream which controls Ca2+ dependent BDNF release. Activation of A2aRs also transactivates TrkB, initiating the TrkB-Akt pathway promoting neuronal survival.
FIGURE 4
FIGURE 4
Schematic figure representing activity-dependent interplay between glutamate-induced excitotoxicity and BDNF-TrkB signaling. The arrival of action potential (step 1), triggers the influx of Ca2+ ions into pre-synaptic terminal (step 2), the rise in intracellular calcium (step 3) in turn triggers the fusion of synaptic vesicles with pre-synaptic membrane to release glutamate (light purple dots) from the terminal (step 4). Membrane depolarization also results in BDNF secretion (orange dots) (step 4) and release pre-synaptically into the synaptic cleft. Dysfunctional glutamate transporters (EAAT2) in ALS results in retention of excessive glutamate in the synaptic cleft (step 5). Post-synaptically, Ca2+ enters through voltage gated calcium channels and via calcium-permeable glutamate receptors (NMDA, green; AMPA magenta; step 6). BDNF binding to TrkB alters the neuronal excitability of ion channels and also enhances post-synaptic glutamate receptor activation causing influx Ca2+ of ions post-synaptically (step 7). Excessive glutamate in the synaptic-cleft over-activates its receptors increasing the intracellular Ca2+ furthermore (step 8). Impaired Na+/Ca2+ exchanger and ATP pumps in SOD1G93A mice results in enhanced Ca2+ intracellularly (DeJesus-Hernandez et al., 2011; Sirabella et al., 2018). Ca2+ released from the intracellular store adds to the Ca2+ concentration (step 8). Enhanced Ca2+ in the post-synaptic neuron also triggers increased Ca2+ dependent secretion and release of BDNF extracellularly causing enhanced BDNF extracellularly (step 9). Trans-activation of TrkB by A2aRs also triggers calcium dependent signaling, activating adenylyl cyclase and leading to increased cAMP and PKA phosphorylation, which in turn influences BDNF secretion (step 10). This increased BDNF in the synaptic cleft binds to its receptors TrkB and repeats the process of Ca2+ influx and modulation of glutamate receptors, eventually leading to Ca2+ overload (step 11) making the neurons hyper-excitable (step 12) which eventually leads to neuronal death (step 13).

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