Research Area

Neurotrophic Factors and Receptors


Neurotrophic Factors and Receptors Overview

Neurotrophic Factors and Receptors

In 1987, Lichtman proposed a nutrient factor, which is believed to be a type of factor involved in survival, growth, migration, and functional association of other cells or axonal regrowth during nerve regeneration. It is named Neurotrophic Factor (NTF). As the study of neurotrophic factors continue to develop, researchers have discovered a large group of neurotrophic factors that are derived from target cells and reverse-nourish neurons. When the peripheral nerve is damaged, the axons of the distal segment have degenerated, the axons of the proximal segment are budded, and the buds gradually grow, eventually forming a connection with the target organ, restoring function and repairing the nerve. In the process, if the support of NTFs is not obtained, the proximal segment will degenerate rapidly, and the cell body will die. Therefore, the research on the growth, development, and protection of nerve cells by the neurotrophic factor family is of great value from the perspective of basic research and clinical research. According to the size of homology, the specificity of gene expression sites and protein action, and the different signaling mechanisms, neurotrophic factors can be divided into three families, nerve growth factor family, ciliary neurotrophic factor family and glial cell source neurotrophic factor family. Changes in NTF levels may lead to neurodegenerative diseases such as Alzheimer's disease (AD) or Huntington's disease, as well as mental disorders such as depression and drug abuse.

Neurotrophic Factors and Receptors Function

Many polypeptide factors can affect the survival, growth, and differentiation of the nervous system. NTF includes nerve growth factor (NGF), brain-derived NTF (BDNF), NTF3, and NTF4, which are widely distributed in the nervous system. These NTF precursors are cleaved by enzymes into mature, stable non-covalent dimers with a molecular weight of 12 to 14 kD. Their level of expression in the brain is usually very low. NTF precursor molecules can be cleaved by intracellular and extracellular proteases such as furin, plasmin, matrix metalloproteinases (MMP) 3 and MMP7, cleavage of the pre-NTF highly conserved amino dicarboxylic acid cleavage site, releasing carbon mature protein. These mature proteins regulate neuronal survival, differentiation, and synaptic plasticity by binding to the tyrosine kinase (Trk) family receptor or the p75NTF receptor (NTFR). Among them, NGF is the first NTF to be discovered. In the central nervous system, it promotes the survival of cholinergic neurons in the basal body and makes it perform its function. These neurons are projected into the hippocampus, and the hippocampus is thought to be closely related to the formation of memory. One of the manifestations of the AD is the decline in memory. Another NTFS is more widely expressed in the central system. Among them, BDNF and NT3 are more involved in the regulation of the survival and function of various neurons in the cortex and hippocampus. NTF can only act on the Trk receptor and/or p75NTFR (belonging to the tumor necrosis factor family). The Trk receptor contains an extracellular binding region, a single transmembrane region, and an intracellular, highly conserved tyrosine kinase region. There are three different subtypes of Trk receptors, TrkA, TrkB, and TrkC. All subtypes have a highly conserved catalytic tyrosine kinase site and a near-membrane phosphorylation site in the cell. All NTFs can bind to the p75 receptor. Although both the Trk receptor and the p75NTR receptor have a ligand-binding region and a cytoplasmic region, the sequences of the two have no similarities. After NTF dimerization, it binds to the Trk receptor, dimerizing the receptor and activating the catalytic tyrosine protein kinase region. The dimerized Trk receptor auto phosphorylates several signaling pathways within the cell. These are tyrosine phosphorylated after recognition of a specific ligand at a recognition site, and they contain a phosphoserine-binding motif such as Src homology region 2 (SH2). The SH2 binding protein linkage activates the Trk receptor to achieve its neurotrophic activity primarily through two distinct intracellular signaling pathways. The major neuronal survival pathways, including the SH2-linked Trk receptor, activate PI3K kinase, increase its phosphorylation level, and then sequentially activate downstream Akts that have multiple functions in the apoptotic program. In addition, Trk receptor phosphorylates SH2 and activates the Ras/red mitogen-activated protein kinase (Ras/MAPK) pathway, which in turn acts on transcription factors such as cyclic adenosine response element binding protein (CREB). CREB proteins play multiple roles in cell cycle, neurite outgrowth, and synaptic plasticity. Similarly, activation of the Trk receptor by phospholipase Cγ (PLC-γ) initiated PLCγ hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2) to generate the IP3 / Ca2+/DAG/PKC signaling pathway. Activation of the Trk receptor can further activate multiple downstream pathways. Each NTF selectively binds to a specific Trk receptor, such as TrkA binding to NGF, NTF3; TrkB binding to BDNF, NTF3, NTF4; TrkC binding to NTF3. P75NTFR, has similar affinity to other NTFS.  Comparing the Trk receptor, p75NTFR receptor is low-affinity receptors. And it interacts with Trk receptors to enhance the recognition of different neurotrophic factors.

Neurotrophic Factors and Receptors Research Status

There is extensive programmed cell death during the development of the nervous system, which determines the number of cells and the correct distribution of neurons during development. NTF is highly expressed early in development and is essential for neuronal survival and selection at different developmental stages. The neurotrophic hypothesis provides a functional analysis of the role of NTF in the development of the nervous system. The nervous system shapes itself to maintain the most competitive and appropriate synaptic connections. A small amount of NTF produced by neurons compressing target cells indicates selective cell survival.  In the central nervous system, repeated expression of multiple NTF receptors and cognate ligands allows for a variety of different linkages that allow the neural network to expand into maturity. In addition, current research has shown that NTF secreted by neurons can also act on itself (autocrine transmission), or it can be transported down to the axon to act on adjacent neurons. At the same time, glial cells can also secrete NTF to neurons through paracrine secretion. In the peripheral nerve, the information transmitted by the NTF reverse signaling pathway must be effectively transmitted over long distances, sometimes even over 1 minute. NTF promotes neuronal survival and differentiation during development, but they can also guide the death of neurons. As a pro-apoptotic receptor, p75NTFR plays a role in the apoptosis of nervous system development and cell damage. During the process of apoptosis, the p75NTFR expression is increased. Binding of BDNF to p75NTFR promotes apoptosis and inhibits the growth of sympathetic neurons. During NTF production, NTF precursors induced apoptosis in p75NTFR-related cells more efficiently than mature NGF. These results indicate that NTF has different function during the process of synthesis, and NTF precursors preferentially activate p75NTFR receptor-mediated apoptosis, whereas mature NTF prefers to bind to Trk receptors and promote neuronal survival. NTF binds to the Trk receptor to mediate neuronal survival, and binding to p75NTFR mediates neuronal apoptosis. If neuronal synapses are not properly connected to the appropriate target, they may become apoptotic. In this way, NTF may not only activate the Trk receptor but also activate p75NTFR, which initiates the process of neuronal death. For example, BDNF binds to p75NTFR in sympathetic neurons lacking the TrkB receptor, directing cell death. Similarly, NTF4 binds to p75NTFR in BDNF-dependent trigeminal neurons and mediates cell death. The presumed reason may be that NT3 binds preferentially to p75NTFR compared to the TrkB receptor. Therefore, activation of Trk or p75NTFR in the same cell can show different results. Cell death mediated by p75NTFR may be important in improving proper neuronal distribution during development. Recent studies have shown that NTF plays an extremely important role in synaptic plasticity in the adult brain. Many neuronal communities rely not only on NTFS that make them viable but also on NTFS that regulate neuronal activity. The structure of the visual dominant column in the cortical layer 4 is strongly influenced by exogenous NTF such as BDNF, indicating the developmental regulation of NTF in the synaptic plasticity of the visual system. In addition, the use of blocking antibodies in the visual system has shown that altering endogenous levels of NTF can dramatically alter its effects. Recent clinical trials have shown limited efficacy in the treatment of neurodegenerative diseases and psychosis directly with NTF. First, delivering enough NTF to target neurons in the body is a major obstacle. Because NTF acts as a macromolecular protein, it is difficult to cross the blood-brain barrier. Second, NTF has a variety of neurological effects in the body. In the central nervous system, the addition of large amounts of indistinguishable NTF can cause unpredictable side effects, such as epilepsy. In addition, in clinical trials, unregulated use of BDNF down-regulates the activity of the TrκB receptor, ultimately leading to a decline in therapeutic efficacy. The new treatment strategy should use NTF in a targeted manner, for example, by an adjustable viral vector. This method has been used in the treatment of AD. First, specific neurons are identified. For example, NGF-dependent neurons at the base undergo neurological regression, and then exogenous NGF is injected into the site to prevent its deterioration. However, exogenous NTF has many shortcomings, including short half-life, unsatisfactory pharmacodynamics; easy to be orally administered by protease hydrolysis; large molecular weight, difficult to pass through the blood-brain barrier, which may cause some side effects such as immune response. Although artificially modified NT can pass the blood-brain barrier, it is costly and difficult to prepare in large quantities. The development of non-polypeptides with neurotrophic small molecule compounds can solve the above problems. Its molecular mass is small, its bioavailability is high, it can penetrate the blood-brain barrier, it is easy to synthesize, and its toxic and side effects are small. It is expected to become a new drug for the treatment of neurodegenerative diseases.

Relationship with Disease

  1. Depression
    At present, depression and its suicide mechanism have not yet been elucidated, and various studies have remained at the hypothesis stage. With the development of molecular biology, in recent years, the global research on the in vivo factors of depression has been widely carried out, and the biological factors of suicidal behavior closely related to it have also received extensive attention. Among them, brain-derived neurotrophic factor (BDNF) has become a hot spot. Domestic and foreign scholars explore the relationship between BDNF levels, gene polymorphisms, methylation changes and other aspects. Many studies have shown that BDNF not only plays an important role in the pathogenesis of depression, but also is closely related to suicidal behavior in patients with depression.
  2. Epilepsy
    The triggering factor for seizures is nerve damage, and seizures further aggravate nerve damage, leading to a vicious circle. Glial cell-derived neurotrophic factor (NTF) has many physiological functions such as promoting the survival of damaged neurons, regulating synaptic plasticity, and stimulating axon growth. Although epileptic damage itself can initiate the neuroprotective mechanism of the central nervous system and promote the release of endogenous NTF, the release of NTF may have short duration and insufficient secretion, so increasing the expression of endogenous NTF secretion will become a direction treatment for the various epilepsy.

References:

  1. Cardoso TDA, Mondin T C, Wiener C D, et al. Neurotrophic Factors, Clinical Features and Gender Differences in Depression. Neurochemical Research. 2014, 39(8):1571-1578.
  2. Bikbova G, Oshitari T, Baba T, et al. Neurotrophic factors for retinal ganglion cell neuropathy - with a special reference to diabetic neuropathy in the retina. Current Diabetes Reviews. 2014, 10(3).
  3. Ogier M, Kron M, Katz D M. Neurotrophic factors in development and regulation of respiratory control. Comprehensive Physiology. 2013, 3(3):1125-1134.
  4. Xiao N, Le Q T. Neurotrophic Factors and Their Potential Applications in Tissue Regeneration. Archivum Immunologiae Et Therapiae Experimentalis. 2016, 64(2):89-99.
  5. Catrina S, Gander B, Madduri S. Nerve conduit scaffolds for discrete delivery of two neurotrophic factors. European Journal of Pharmaceutics & Biopharmaceutics. 2013, 85(1):139-142.

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