Neurotrophins are a family of proteins that induce the survival, development, and function of neurons .
69-409: 3EWV , 2N80 , 2N97 , 2N83 4804 18053 ENSG00000064300 ENSMUSG00000000120 P08138 Q9Z0W1 NM_002507 NM_033217 NP_002498 NP_150086 The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor . p75NTR
138-456: A licensed medicine in China since 2003. There is evidence of improved patient outcomes for several diseases of the nervous system, including acute intracerebral hemorrhage, global developmental delay, optic atrophy, epilepsy and cerebral palsy. This is significant as there are few medicines which can treat injuries and diseases of the nervous system. Research and clinical use outside of China
207-615: A ligand bound activates RhoA and limits actin assembly, but neurotrophin binding to p75NTR can inactivate RhoA and promote actin assembly. p75NTR associates with the Rho GDP dissociation inhibitor (RhoGDI) , and RhoGDI associates with RhoA . Interactions with Nogo can strengthen the association between p75NTR and RhoGDI. Neurotrophin binding to p75NTR inhibits the association of RhoGDI and p75NTR, thereby suppressing RhoA release and promoting growth cone elongation (inhibiting RhoA actin suppression). Neurotrophin binding to p75NTR activates
276-493: A person's daily life and activities. The neuropathological hallmarks of AD include amyloid plaques and neurofibrillary tangles, which lead to neuronal death. Studies in animal models of AD have shown that p75NTR contributes to amyloid β-induced neuronal damage. In humans with AD, increases in p75NTR expression relative to TrkA have been suggested to be responsible for the loss of cholinergic neurons. Increases in proNGF in AD indicate that
345-595: A physiological role for this is unknown. It has also been found in several snake venoms. In the peripheral and central neurons, neurotrophins are important regulators for survival, differentiation, and maintenance of nerve cells. They are small proteins that secrete into the nervous system to help keep nerve cells alive. There are two distinct classes of glycosylated receptors that can bind to neurotrophins. These two proteins are p75 (NTR), which binds to all neurotrophins, and subtypes of Trk , which are each specific for different neurotrophins. The reported structure above
414-400: A proNT (proNGF or proBDNF) to p75NTR and its sortilin co-receptor (which binds the pro-domain of proNTs) causes a p75NTR-dependent signal transduction cascade. The cleaved death domain of p75NTR activates c-Jun N-terminal kinase (JNK). The activated JNK translocates into the nucleus , where it phosphorylates and transactivates c-Jun . The transactivation of c-Jun results in
483-467: A property that facilitates Neurotrophin binding. The intracellular part is a global-like domain, known as a death domain, which consists of two sets of perpendicular helixes arranged in sets of three. It connects the transmembrane domain through a flexible linker region N-terminal domain. It is important to say that, in contrast to the type I death domain found in other TNFR proteins, the type II intracellular death domain of p75NTR does not self-associate. This
552-843: A reduced migration, tumorigenicity, proliferation and induction of apoptosis. Furthermore, increased levels of CD271 were observed in brain metastatic melanoma cells whereas resistance to the BRAF inhibitor vemurafenib supposedly selects for highly malignant brain and lung-metastasizing melanoma cells. Recently, expression of p75NTR (NGFR) was associated with progressive intracranial disease in melanoma patients Low-affinity nerve growth factor receptor has been shown to interact with: Nerve growth factor 4ZBN , 1SG1 , 1WWW , 2IFG , 4EDW , 4EDX 4803 18049 ENSG00000134259 ENSMUSG00000027859 P01138 P01139 NM_002506 NM_001112698 NM_013609 NP_002497 NP_001106168 NP_038637 Nerve growth factor ( NGF )
621-462: A role in mediating p75NTR-dependent survival, but one of the more intriguing possibilities is that Ant-induced phosphorylation of IkB kinase 1 (IKK1) plays a role in the induction of NF-kB. Proforms of NGF and BDNF (proNGF and proBDNF) are precursors to NGF and BDNF. proNGF and proBDNF interact with p75NTR and cause p75NTR-mediated apoptosis without activating TrkA-mediated survival mechanisms. Cleavage of proforms into mature Neurotrophins allows
690-443: Is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons . It is perhaps the prototypical growth factor , in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being
759-491: Is a neurotrophic factor receptor . Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor , Neurotrophin-3 , Brain-derived neurotrophic factor , and Neurotrophin-4 . All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR
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#1732779894799828-399: Is a 2.6 Å-resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75 (NRT), forming a symmetrical crystal structure. There are two classes of receptors for neurotrophins: p75 and the "Trk" family of Tyrosine kinases receptors. Nerve growth factor (NGF), the prototypical growth factor , is a protein secreted by a neuron's target cell. NGF
897-526: Is a transcription factor that can be activated by p75NTR. Nerve growth factor (NGF) is a neurotrophin that promotes neuronal growth, and, in the absence of NGF, neurons die. Neuronal death in the absence of NGF can be prevented by NF-kB activation. Phosphorylated IκB kinase binds to and activates NF-kB before separating from NF-kB. After separation, IκB degrades and NF-kB continues to the nucleus to initiate pro-survival transcription. NF-kB also promotes neuronal survival in conjunction with NGF. NF-kB activity
966-416: Is activated by p75NTR, and is not activated via Trk receptors . NF-kB activity does not effect Brain-derived neurotrophic factor promotion of neuronal survival. p75NTR serves as a regulator for actin assembly. Ras homolog family member A ( RhoA ) causes the actin cytoskeleton to become rigid which limits growth cone mobility and inhibits neuronal elongation in the developing nervous system. p75NTR without
1035-544: Is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate. Exercise has been shown to increase the amount of BDNF and therefore serve as a vehicle for neuroplasticity. Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-family of neurotrophins. It is a protein growth factor that has activity on certain neurons of
1104-465: Is age-related and correlates with proliferative potential of neural progenitors. p75NTR has been implicated as a marker for cancer stem cells in melanoma and other cancers. Melanoma cells transplanted into an immunodeficient mouse model were shown to require expression of CD271 in order to grow a melanoma. Gene knockdown of CD271 has also been shown to abolish neural crest stem cell properties of melanoma cells and decrease genomic stability leading to
1173-495: Is an unusual member of this family due to its propensity to dimerize rather than trimerize, because of its ability to act as a tyrosine kinase co-receptor, and because the neurotrophins are structurally unrelated to the ligands, which typically bind TNFR family members. Indeed, with the exception of p75NTR, essentially all members of the TNFR family preferentially bind structurally related trimeric Type II transmembrane ligands, members of
1242-440: Is constitutively active, neurons survive even without NGF. A second pathway contributing to cell survival occurs through activation of the mitogen-activated protein kinase ( MAPK ) kinase. In this pathway, recruitment of a guanine nucleotide exchange factor by the adaptor and docking proteins leads to activation of a membrane-associated G-protein known as Ras . The guanine nucleotide exchange factor mediates Ras activation through
1311-401: Is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor TrkA on the neuron, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the neuron's cell body . This movement of NGF from axon tip to soma is thought to be involved in
1380-485: Is dependent on the presence of neurotrophins. The expression of TrkB, which is found mainly in the CNS, does not cause apoptosis. This is thought to be because it is differentially located in the cell membrane while TrkA and TrkC are co-localized with p75NTR in lipid rafts . In the PNS (where NGF, NT-3 and NT-4 are mainly secreted) cell fate is determined by a single growth factor (i.e. neurotrophins). However, in
1449-455: Is evidence that pancreatic beta cells express both the TrkA and p75NTR receptors of NGF. It has been shown that the withdrawal of NGF induces apoptosis in pancreatic beta cells, signifying that NGF may play a critical role in the maintenance and survival of pancreatic beta cells. NGF plays a critical role in the regulation of both innate and acquired immunity. In the process of inflammation , NGF
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#17327798947991518-459: Is involved in pathways that promote neuronal survival and neuronal death. p75NTR is a member of the tumor necrosis factor receptor superfamily . p75NTR/LNGFR was the first member of this large family of receptors to be characterized, that now contains about 25 receptors, including tumor necrosis factor 1 (TNFR1) and TNFR2, Fas, RANK, and CD40. All members of the TNFR superfamily contain structurally related cysteine-rich modules in their ECDs. p75NTR
1587-504: Is limited despite a large body of evidence supporting its use. Recombinant human nerve growth factor (rhNGF; named cenegermin ) has been formulated as an eye drop (0.002%). In 2018 it was approved by the FDA for the treatment of neurotrophic keratitis , a disease in which corneal nerves are damaged or nonfunctional. Without normal corneal sensation, the corneal epithelium does not heal after injury or infection, leading to melting of
1656-531: Is linked to reduced numbers of dendritic spines in the hippocampus, likely through p75NTR interactions with Transforming protein RhoA . Modulating p75NTR function could be a future direction in treating Huntington's disease. Amyotrophic lateral sclerosis ALS is a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. One study using
1725-673: Is released in high concentrations by mast cells , and induces axonal outgrowth in nearby nociceptive neurons. This leads to increased pain perception in areas under inflammation. In acquired immunity, NGF is produced by the Thymus as well as CD4+ T cell clones , inducing a cascade of maturation of T cells under infection. NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals e.g. "induced" ovulators, such as llamas. Surprisingly, research showed that these induced animals will also ovulate when semen from on-schedule or "spontaneous" ovulators, such as cattle
1794-516: Is required for apoptosis but c-jun , a protein in the JNK signaling pathway, is not always required. LNGFR also activates a caspase -dependent signaling pathway that promotes developmental axon pruning, and axon degeneration in neurodegenerative disease. In the apoptosis pathway, members of the TNF receptor superfamily assemble a death-inducing signaling complex (DISC) in which TRADD or FADD bind directly to
1863-423: Is required for many apoptosis-promoting p75NTR reactions, functioning as a co-receptor for the binding of neurotrophins such as BDNF . pro-neurotrophins (such as proBDNF) bind especially well to p75NTR when sortilin is present. When p75NTR initiates apoptosis, NGF binding to Tropomyosin receptor kinase A (TrkA) can negate p75NTR apoptotic effects. p75NTR c-Jun kinase pathway activation (which causes apoptosis)
1932-545: Is suppressed when NGF binds to TrkA. p75NTR activation of NF-kB , which promotes survival, is unaffected by NGF binding to TrkA. p75NTR functions in a complex with Nogo-66 receptor (NgR1) to mediate RhoA-dependent inhibition of growth of regenerating axons exposed to inhibitory proteins of CNS myelin, such as Nogo , MAG or OMgP . Without p75NTR, OMgP can activate RhoA and inhibit CNS axon regeneration. Coexpression of p75NTR and OMgP suppress RhoA activation. A complex of NgR1, p75NTR and LINGO1 can activate RhoA. NF-kB
2001-408: Is used. Its significance in humans is unknown. It was previously dubbed ovulation-inducing factor (OIF) in semen before it was identified as beta-NGF in 2012. NGF binds with at least two classes of receptors: the tropomyosin receptor kinase A (TrkA) and low-affinity NGF receptor (LNGFR/p75NTR). Both are associated with neurodegenerative disorders . When NGF binds to the TrkA receptor, it drives
2070-588: The GDNF family of ligands , and ciliary neurotrophic factor (CNTF), among other biomolecules . Neurotrophin-6 and neurotrophin-7 also exist, but are only found in zebrafish . During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells. Such cells control their degree of innervation (the number of axon connections) by
2139-540: The United States National Library of Medicine 's medical subject headings , the term neurotrophin may be used as a synonym for neurotrophic factor , but the term neurotrophin is more generally reserved for four structurally related factors: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). The term neurotrophic factor generally refers to these four neurotrophins,
Low-affinity nerve growth factor receptor - Misplaced Pages Continue
2208-435: The c-Jun N-terminal kinases (JNK) signaling pathway causing apoptosis of developing neurons. JNK, through a series of intermediates, activates p53 and p53 activates Bax which initiates apoptosis. TrkA can prevent p75NTR-mediated JNK pathway apoptosis. JNK can directly phosphorylate Bim-EL, a splicing isoform of Bcl-2 interacting mediator of cell death (Bim) , which activates Bim-EL apoptotic activity. JNK activation
2277-401: The p75NTR . The PCD which occurs during brain development is responsible for the loss of a majority of neuroblasts and differentiating neurons. It is necessary because during development there is a massive over production of neurons which must be killed off to attain optimal function. In the development of both the peripheral nervous system (PNS) and the central nervous system (CNS)
2346-592: The primary structure of NGF. This eventually led to the discovery of the NGF gene. NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals. Nerve Growth Factors (NGF) were initially discovered due to their actions during development, but NGF are now known to be involved in the function throughout the life of the animal. Nerve growth factor has been shown to interact with Tropomyosin receptor kinase A . NGF, specifically mouse (murine) nerve growth factor, has been available as
2415-653: The 1950s while faculty members at Washington University in St. Louis . The critical discover was done by Levi-Montalcini and Hertha Meyer at the Carlos Chagas Filho Biophysics Institute of the Federal University of Rio de Janeiro in 1952. Their publication in 1954 became the definitive proof for the existence of the protein. Levi-Montalcini later remarked: The tumor had given a first hint of its existence in St. Louis but it
2484-431: The CNS (where BDNF is mainly secreted in the spinal cord , substantia nigra , amygdala , hypothalamus , cerebellum , hippocampus and cortex ) more factors determine cell fate, including neural activity and neurotransmitter input. Neurotrophins in the CNS have also been shown to play a more important role in neural cell differentiation and function rather than survival. For these reasons, compared to neurons in
2553-523: The CNS. The viability of these mice was moderate. The NT-4-knockout mice had moderate losses of their nodose petrosal ganglia and minor losses of their DRG, trigeminal ganglia and vestibular ganglia. The NT-4-knockout mice also had minor losses of facial motoneurons. These mice were very viable. The NT-3 knockout mice had losses of a majority of their DRG, trigeminal ganglia, cochlear ganglia and superior cervical ganglia and moderate losses of nodose petrosal ganglia and vestibular ganglia. In addition
2622-640: The GDP-GTP exchange process. The active Ras protein phosphorylates several proteins, along with the serine/threonine kinase, Raf . Raf in turn activates the MAPK cascade to facilitate ribosomal s6 kinase (RSK) activation and transcriptional regulation. Both Akt and RSK, components of the PI3K-Akt and MAPK pathways respectively, act to phosphorylate the cyclic AMP response element binding protein ( CREB ) transcription factor. Phosphorylated CREB translocates into
2691-474: The Neurotrophin environment is favorable for p75NTR/sortilin signaling and supports the theory that age-related neural damage is facilitated by a shift toward proNGF-mediated signaling. A recent study found that activation of Ngfr signaling in astroglia of Alzheimer's disease mouse model enhanced neurogenesis and reduced two hallmarks of Alzheimer's disease. This study also found that NGFR signaling in humans
2760-489: The PNS, neurons of the CNS are less sensitive to the absence of a single neurotrophin or neurotrophin receptor during development; with the exception being neurons in the thalamus and substantia nigra . Gene knockout experiments were conducted to identify the neuronal populations in both the PNS and CNS that were affected by the loss of different neurotrophins during development and the extent to which these populations were affected. These knockout experiments resulted in
2829-475: The TNF ligand superfamily. p75NTR is a type I transmembrane protein , with a molecular weight of 75 kDa, determined by glycosylation through both N- and O-linkages in the extracellular domain. It consists of an extracellular domain, a transmembrane domain and an intracellular domain. The extracellular domain consists of a stalk domain connecting the transmembrane domain and four cysteine-rich repeat domains, CRD1, CRD2, CRD3, and CRD4; which are negatively charged,
Low-affinity nerve growth factor receptor - Misplaced Pages Continue
2898-561: The Trk receptor complex-recruitment of a second adaptor protein called growth factor-receptor bound protein-2 ( Grb2 ) along with a docking protein called Grb2-associated Binder-1 ( GAB1 ). Subsequently, phosphatidylinositol-3 kinase ( PI3K ) is activated, resulting in Akt kinase activation. Study results have shown that blocking PI3K or Akt activity results in death of sympathetic neurons in culture, regardless of NGF presence. However, if either kinase
2967-508: The TrkA and p75 with high affinity (around 5 nM), and hence as so-called "microneurotrophins". DHEA has also been found to bind to the TrkB and TrkC, though while it activated the TrkC, it was unable to activate the TrkB. It has been proposed that DHEA may have been the ancestral ligand of the Trk receptors early on in the evolution of the nervous system , eventually being superseded by
3036-447: The absence of Trk receptors due to the fact that activated Trk receptors suppress the JNK cascade. The expression of TrkA or TrkC receptors in the absence of neurotrophins can lead to apoptosis, but the mechanism is poorly understood. The addition of NGF (for TrkA) or NT-3 (for TrkC) prevents this apoptosis. For this reason TrkA and TrkC are referred to as dependence receptors , because whether they induce apoptosis or survival
3105-471: The activation of PI 3-kinase , ras , and PLC signaling pathways. Alternatively, the p75NTR receptor can form a heterodimer with TrkA, which has higher affinity and specificity for NGF. Studies suggest that NGF circulates throughout the entire body via the blood plasma, and is important for the overall maintenance of homeostasis . Binding interaction between NGF and the TrkA receptor facilitates receptor dimerization and tyrosine residue phosphorylation of
3174-519: The associated neuron from initiating programmed cell death – allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells , to form neurons. Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain (for example, the hippocampus ) retain the ability to grow new neurons from neural stem cells , a process known as neurogenesis . Neurotrophins are chemicals that help to stimulate and control neurogenesis. According to
3243-565: The brain, it is active in the hippocampus , cortex , cerebellum , and basal forebrain – areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3. BDNF is one of the most active substances to stimulate neurogenesis. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development . Despite its name, BDNF
3312-548: The corneal stroma and recurrent infections. Clinical trials of cenegermin indicate that the drug can increase the rate of healing of the epithelium. Neurotrophin They belong to a class of growth factors , secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors . Neurotrophic factors are secreted by target tissue and act by preventing
3381-453: The cytoplasmic tail by adjacent Trk receptors. Trk receptor phosphorylation sites operate as Shc adaptor protein docking sites, which undergo phosphorylation by the TrkA receptor Once the cytoplasmic adaptor protein (Shc) is phosphorylated by the receptor cytoplasmic tail, cell survival is initiated through several intracellular pathways. One major pathway leads to the activation of the serine/threonine kinase, Akt . This pathway begins with
3450-698: The death domain of the p75NTR cytoplasmic tail. Survival occurs when recruited cytoplasmic adaptor proteins facilitate signal transduction through tumor necrosis factor receptor members such as TRAF6 , which results in the release of nuclear factor κB ( NF-κB ) transcription activator. NF-κB regulates nuclear gene transcription to promote cell survival. Alternatively, programmed cell death occurs when TRAF6 and neurotrophin receptor interacting factor (NRIF) are both recruited to activate c-Jun N-terminal kinase (JNK); which phosphorylates c-Jun. The activated transcription factor c-Jun regulates nuclear transcription via AP-1 to increase pro-apoptotic gene transcription. There
3519-571: The homodimerization of the receptor, which in turn causes the autophosphorylation of the tyrosine kinase segment. The tropomyosin receptor kinase A receptor has five extracellular domains, and the fifth domain is sufficient in binding NGF. Once bound, the complex undergoes endocytosis and activates the NGF transcriptional program, following two major pathways, the Ras/MAPK pathway and the PI3K/Akt pathway . The binding of NGF to TrkA also leads to
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#17327798947993588-486: The long-distance signaling of neurons. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain , but also found in the periphery. To be specific, it is a protein that has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In
3657-570: The loss of several neuron populations including the retina , cholinergic brainstem and the spinal cord . It was found that NGF-knockout mice had losses of a majority of their dorsal root ganglia (DRG), trigeminal ganglia and superior cervical ganglia . The viability of these mice was poor. The BDNF-knockout mice had losses of a majority of their vestibular ganglia and moderate losses of their DRG, trigeminal ganglia, nodose petrosal ganglia and cochlear ganglia. In addition they also had minor losses of their facial motoneurons located in
3726-483: The mature NGF and BDNF to activate TrkA-mediated survival mechanisms. Recent research has suggested a number of roles for the LNGFR, including in development of the eyes and sensory neurons, and in repair of muscle and nerve damage in adults. Two distinct subpopulations of Olfactory ensheathing glia have been identified with high or low cell surface expression of low-affinity nerve growth factor receptor (p75). Sortilin
3795-428: The nucleus and mediates increased expression of anti-apoptotic proteins, thus promoting NGF-mediated cell survival. However, in the absence of NGF, the expression of pro-apoptotic proteins is increased when the activation of cell death-promoting transcription factors such as c-Jun are not suppressed by the aforementioned NGF-mediated cell survival pathways. Rita Levi-Montalcini and Stanley Cohen discovered NGF in
3864-504: The p75NTR-neurotrophin binding activates multiple intracellular pathways which are important in regulating apoptosis. Proneurotrophins (proNTs) are neurotrophins which are released as biologically active uncleaved pro-peptides . Unlike mature neurotrophins which bind to the p75NTR with a low affinity, proNTs preferentially bind to the p75NTR with high affinity. The p75NTR contains a death domain on its cytoplasmic tail which when cleaved activates an apoptotic pathway. The binding of
3933-408: The peripheral and central nervous system ; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses . NT-3 is the third neurotrophic factor to be characterized, after NGF and BDNF. NT-3 is unique among the neurotrophins in the number of neurons it has potential to stimulate, given its ability to activate two of
4002-458: The polypeptide neurotrophins. During neuron development neurotrophins play a key role in growth, differentiation , and survival. They also play an important role in the apoptotic programmed cell death (PCD) of neurons. Neurotrophic survival signals in neurons are mediated by the high-affinity binding of neurotrophins to their respective Trk receptor. In turn, a majority of neuronal apoptotic signals are mediated by neurotrophins binding to
4071-403: The protein into functional NGF. The term nerve growth factor usually refers to the 2.5S, 26-kDa beta subunit of the protein, the only component of the 7S NGF complex that is biologically active (i.e. acting as a signaling molecule). As its name suggests, NGF is involved primarily in the growth, as well as the maintenance, proliferation, and survival of nerve cells (neurons) and is critical for
4140-586: The receptor tyrosine kinase neurotrophin receptors ( TrkC and TrkB ). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons. Neurotrophin-4 (NT-4) is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase . It is also known as NT4, NT5, NTF4, and NT-4/5. The endogenous steroids dehydroepiandrosterone (DHEA) and its sulfate ester , DHEA sulfate (DHEA-S), have been identified as small-molecule agonists of
4209-639: The receptor's death domain, thereby allowing aggregation and activation of Caspase 8 and subsequent activation of the Caspase cascade. However, Caspase 8 induction does not appear to be involved in p75NTR-mediated apoptosis, but Caspase 9 is activated during p75NTR-mediated killing. Huntington's disease is characterized by cognitive impairments. There is increased expression of p75NTR in the hippocampus of Huntington's disease patients (including mice models and humans). Over expression of p75NTR in mice causes cognitive impairments similar to Huntington's disease. p75NTR
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#17327798947994278-399: The secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF or beta-NGF), a vertebrate protein that stimulates division and differentiation of sympathetic and embryonic sensory neurons. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although
4347-811: The site 1 that contains five hydrogen bonds and one salt bridge. Site 2 is formed by equal contributions from CDR3 and CRD4 and involves two salt bridges and two hydrogen bonds. Site 3, in the CRD4, includes only one salt bridge. Neurotrophins that interact with p75NTR include NGF , NT-3 , BDNF , and NT-4/5 . Neurotrophins activating p75NTR may initiate apoptosis (for example, via c-Jun N-terminal kinases signaling, and subsequent p53, Jax-like proteins and caspase activation). This effect can be counteracted by anti-apoptotic signaling by TrkA . Neurotrophin binding to p75NTR, in addition to apoptotic signaling, can also promote neuronal survival (for example, via NF-kB activation). There are multiple targets of Akt that could play
4416-492: The superoxide dismutase 1 (SOD1) mutant mouse, an ALS model which develops severe neurodegeneration, the expression of p75NTR correlated with the extent of degeneration and p75NTR knockdown delayed disease progression. Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD is a neurodegenerative disease characterized by the loss of cognitive functioning - thinking, remembering and reasoning- and behavioral abilities to such an extent that it interferes with
4485-881: The survival and maintenance of sympathetic and sensory neurons as they undergo apoptosis in its absence. However, several recent studies suggest that NGF is also involved in pathways besides those regulating the life cycle of neurons. NGF can drive the expression of genes such as bcl-2 by binding to the Tropomyosin receptor kinase A , which stimulates the proliferation and survival of the target neuron. High affinity binding between proNGF, sortilin, and p75NTR can result in either survival or programmed cell death . Study results indicate that superior cervical ganglia neurons that express both p75NTR and TrkA die when treated with proNGF, while NGF treatment of these same neurons results in survival and axonal growth. Survival and PCD mechanisms are mediated through adaptor protein binding to
4554-462: The survival of pancreatic beta cells and the regulation of the immune system . NGF is initially in a 7S, 130- kDa complex of 3 proteins – Alpha-NGF, Beta-NGF, and Gamma-NGF (2:1:2 ratio) when expressed. This form of NGF is also referred to as proNGF (NGF precursor). The gamma subunit of this complex acts as a serine protease, and cleaves the N-terminal of the beta subunit, thereby activating
4623-424: The transcription of pro-apoptotic factors TFF-a , Fas-L and Bak . The importance of sortilin in p75NTR-mediated apoptosis is exhibited by the fact that the inhibition of sortilin expression in neurons expressing p75NTR suppresses proNGF-mediated apoptosis, and the prevention of proBDNF binding to p75NTR and sortilin abolished apoptotic action. Activation of p75NTR-mediated apoptosis is much more effective in
4692-451: Was an early indication that p75NTR does not signal death through the same mechanism as the TNFR death domains, although the ability of the p75NTR death domain to activate other second messengers is conserved. The p75ECD-binding interface to NT-3 can be divided into three main contact sites, two in the case of NGF, that are stabilized by hydrophobic interactions, salt bridges, and hydrogen bonds. The junction regions between CDR1 and CDR2 form
4761-639: Was in Rio de Janeiro that it revealed itself, and it did so in a theatrical and grand way, as if spurred by the bright atmosphere of that explosive and exhuberant manifestation of life that is the Carnival in Rio. However, its discovery, along with the discovery of other neurotrophins, was not widely recognized until 1986, when it won the Nobel Prize in Physiology or Medicine. Studies in 1971 determined
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