The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons, and have since been shown to control a number of aspects of survival, development and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, all neurotrophins activate the p75 neurotrophin receptor (p75(NTR)), a member of the tumour necrosis factor receptor superfamily. Nerve growth factor (NGF), the best characterised member of the neurotrophin family, sends its survival signals through activation of TrkA and can induce death by binding to p75(NTR). Neurotrophin engagement of Trk receptors leads to activation of Ras, phosphatidylinositol 3-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, including the mitogen-activated protein kinases. Neurotrophin availability is required into adulthood, where they control synaptic function and plasticity, and sustain neuronal cell survival, morphology and differentiation. Preclinical studies point to the therapeutic potential of neurotrophic factors in preventing or slowing the progression of neurodegenerative conditions. Given the difficulties inherent with a protein therapeutic approach to treating central nervous system disorders, increasing attention has turned to the development of alternative strategies and, in particular, small molecule mimetics. This article will provide an overview of neurotrophin biology, their receptors, and signalling pathways, followed by a description of functional mimetics of neurotrophins acting at Trk receptors. Moreover, exciting recent data describing G-protein-coupled receptor transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects.
"It has been shown that neurotrophins, especially NGF and BDNF, can have a neuroprotective effect in AD-like conditions (Wang et al., 2002; Skaper, 2008; Bruno et al., 2009). NGF injection prevents degeneration of cholinergic neurons after fornix lesion or administration of toxins (Williams et al., 1986; Koliatsos et al., 1990; Charles et al., 1996; Blesch et al., 2005; Skaper, 2008). Successful experiments on NGF-producing fibroblasts transplantation into the affected brain structures were reported (Rosenberg et al., 1988; Chen and Gage, 1995; Tuszynski et al., 1996). "
"neurotrophin receptor expression levels are downregulated , and neurotrophin expression appears to partially parallel these decreases, possible interventions include gene therapy (Tuszynski 2002, 2007; Maeder et al., 2013), modifications in target-derived neurotrophic support (Cooper et al., 2001; Howe and Mobley, 2004; Salehi et al., 2006) and, potentially, receptor transactivation (Rajagopal et al., 2004; Skaper, 2008; Huang and McNamara, 2012) to increase TrkA, TrkB, and/or TrkC signaling for pro-survival effects. Importantly, increasing neurotrophic support can be used in conjunction with so-called monotherapies that aim to modify amyloid and/or tau levels in AD and DS (D'Alton and George, 2011; Lane et al., 2012) for a more sophisticated treatment regimen with a higher likelihood of success by affecting multiple targets during the presumed prodromal and neurodegenerative phases of DS and AD. "
"Neurotrophins (NTs) such as nerve growth factor (NGF), brain-derived neurotrophic factor, NT-3, and NT-4 are a family of closely related proteins that regulate cell survival, death, maintenance, and development in both the central and peripheral nervous systems  . The effects of NTs are exhibited through activation of two distinct receptor types: the tropomyosin-related kinase (Trk) subfamily (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75NTR) that belongs to the tumor necrosis factor receptor superfamily . NGF activates various intracellular signaling pathways through activation of the TrkA and p75NTR receptors, involved in the regulation of both cell survival and death in neuronal and non-neuronal cell types. "
[Show abstract][Hide abstract] ABSTRACT: The c-Jun N-terminal kinase (JNK) has been well known to play an important role in cell death signaling of the p75 neurotrophin receptor. However, little has been studied about a role of JNK in the signaling pathways of the tropomyosin-related kinase A (TrkA) neurotrophin receptor. In this study, we investigated JNK inhibitor SP600125-controlled TrkA-dependent targets by proteomic analysis to better understand an involvement of JNK in TrkA-mediated signaling pathways. PDQuest image analysis and protein identification results showed that hnRNP C1/C2, α-tubulin, β-tubulin homologue, actin homologue, and eIF-5A-1 protein spots were upregulated by ectopic expression of TrkA, whereas α-enolase, peroxiredoxin-6, PROS-27, HSP70, PP1-gamma, and PDH E1-alpha were downregulated by TrkA, and these TrkA-dependent upregulation and downregulation were significantly suppressed by SP600125. Notably, TrkA largely affected certain posttranslational modification(s) but not total protein amounts of the SP600125-controlled TrkA-dependent targets. Moreover, SP600125 strongly suppressed TrkA-mediated tyrosine phosphorylation signaling pathways as well as JNK signaling, indicating that SP600125 could function as a TrkA inhibitor. Taken together, our results suggest that TrkA could play an important role in the cytoskeleton, cell death, cellular processing, and glucose metabolism through activation or inactivation of the SP600125-controlled TrkA-dependent targets. This article is protected by copyright. All rights reserved.
Xianjin Ke, Qian Li, Li Xu, Ying Zhang, Dongmei Li, Jianhua Ma, Xiaoming Mao
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