Neurotropin promotes NGF signaling through interaction of GM1 ganglioside with Trk neurotrophin receptor in PC12 cells

Fukuda, Yu; Fukui, Takao; Hikichi, Chika; Ishikawa, Tomomasa; Murate, Kenichiro; Adachi, Takeshi; Imai, Hideki; Fukuhara, Kazunobu; Ueda, Akihiro; Kaplan, Allen P.; Mutoh, Tatsuro

doi:10.1016/j.brainres.2014.11.041

Cited by 30 publications

(16 citation statements)

References 44 publications

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“…The neurite sprouting and the expression of neurofilaments are markers of neuronal differentiation (Fukuda et al . ), and we conclude that the effect exerted by II 3 Neu5Ac‐Gg 4 on N2a cells overlaps to that previously reported for ganglioside GM1 (Facci et al . ).…”

Section: Discussionsupporting

confidence: 89%

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Role of theGM1 ganglioside oligosaccharide portion in the TrkA‐dependent neurite sprouting in neuroblastoma cells

Chiricozzi

Pomè

Maggioni

et al. 2017

Journal of Neurochemistry

115

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GM1 ganglioside (II NeuAc-Gg Cer) is known to promote neurite formation in neuroblastoma cells by activating TrkA-MAPK pathway. The molecular mechanism by which GM1 is involved in the neurodifferentiation process is still unknown, however, in vitro and in vivo evidences have suggested that the oligosaccharide portion of this ganglioside could be involved. Here, we report that, similarly to the entire GM1 molecule, its oligosaccharide II NeuAc-Gg rather than its ceramide (Cer) portion is responsible for the neurodifferentiation process by augmenting neurite elongation and increasing the neurofilament protein expression in murine neuroblastoma cells, Neuro2a. Conversely, asialo-GM1, GM2 and GM3 oligosaccharides are not effective in neurite elongation on Neuro2a cells, whereas the effect exerted by the Fuc-GM1 oligosaccharide (IV αFucII Neu5Ac-Gg ) is similar to that exerted by GM1 oligosaccharide. The neurotrophic properties of GM1 oligosaccharide are exerted by activating the TrkA receptor and the following phosphorylation cascade. By photolabeling experiments performed with a nitrophenylazide containing GM1 oligosaccharide, labeled with tritium, we showed a direct interaction between the GM1 oligosaccharide and the extracellular domain of TrkA receptor. Moreover, molecular docking analyses confirmed that GM1 oligosaccharide binds the TrkA-nerve growth factor complex leading to a binding free energy of approx. -11.5 kcal/mol, acting as a bridge able to increase and stabilize the TrkA-nerve growth factor molecular interactions.

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Section: Discussionsupporting

confidence: 89%

“…Expression of heavy, medium, and light intracellular NF subunits (NF‐H, NF‐M and NF‐L), considered markers of neurodifferentiation (Fukuda et al . ), was evaluated by immunoblotting. NF proteins are considered the major components of cytoskeleton supporting axonal construction.…”

Section: Resultsmentioning

confidence: 99%

Role of theGM1 ganglioside oligosaccharide portion in the TrkA‐dependent neurite sprouting in neuroblastoma cells

Chiricozzi

Pomè

Maggioni

et al. 2017

Journal of Neurochemistry

115

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“…SCs distal to the injury site dedifferentiate, proliferate, and line the endoneurial tubes to guide regenerating axons, finally re-differentiating to the myelination stage after guiding axons toward the target [ 29 ]. Previous studies on neurons demonstrated that NTP promotes neurite outgrowth in PC12 cells [ 30 , 31 ], and attenuates the inhibition of neurite outgrowth induced by paclitaxel or oxaliplatin in PC12 cells and DRG neurons [ 32 , 33 ]. Amelioration of demyelination in the chronic constriction injury model [ 15 ] and recovery in a paclitaxel-induced demyelination model [ 32 ] were also observed.…”

Section: Discussionmentioning

confidence: 99%

Neurotropin® Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model

Matsuoka

Tanaka

Sayanagi

et al. 2018

IJMS

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Neurotropin® (NTP), a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs) in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT) activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases.

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“…We recently reported that expressions of neurotrophins were enhanced in human neuroblastoma SH-SY5Y cells by NTP through activation of autocrine pathways depending on TrkB activity [ 16 ]. In subsequent studies using rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells) [ 24 ], NTP was shown to facilitate the TrkA-mediated neurotrophin signaling pathway [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection by Neurotropin through Crosstalk of Neurotrophic and Innate Immune Receptors in PC12 Cells

Fukuda

Nakajima

Mutoh

2020

IJMS

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Infected or damaged tissues release multiple “alert” molecules such as alarmins and damage-associated molecular patterns (DAMPs) that are recognized by innate immune receptors, and induce tissue inflammation, regeneration, and repair. Recently, an extract from inflamed rabbit skin inoculated with vaccinia virus (Neurotropin®, NTP) was found to induce infarct tolerance in mice receiving permanent ischemic attack to the middle cerebral artery. Likewise, we report herein that NTP prevented the neurite retraction in PC12 cells by nerve growth factor (NGF) deprivation. This effect was accompanied by interaction of Fyn with high-affinity NGF receptor TrkA. Sucrose density gradient subcellular fractionation of NTP-treated cells showed heretofore unidentified membrane fractions with a high-buoyant density containing Trk, B subunit of cholera toxin-bound ganglioside, flotillin-1 and Fyn. Additionally, these new membrane fractions also contained Toll-like receptor 4 (TLR4). Inhibition of TLR4 function by TAK-242 prevented the formation of these unidentified membrane fractions and suppressed neuroprotection by NTP. These observations indicate that NTP controls TrkA-mediated signaling through the formation of clusters of new membrane microdomains, thus providing a platform for crosstalk between neurotrophic and innate immune receptors. Neuroprotective mechanisms through the interaction with innate immune systems may provide novel mechanism for neuroprotection.

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Neurotropin promotes NGF signaling through interaction of GM1 ganglioside with Trk neurotrophin receptor in PC12 cells

Cited by 30 publications

References 44 publications

Role of theGM1 ganglioside oligosaccharide portion in the TrkA‐dependent neurite sprouting in neuroblastoma cells

Role of theGM1 ganglioside oligosaccharide portion in the TrkA‐dependent neurite sprouting in neuroblastoma cells

Neurotropin® Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model

Neuroprotection by Neurotropin through Crosstalk of Neurotrophic and Innate Immune Receptors in PC12 Cells

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