Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Khairunnuur Fairuz Azman
 -- 1225 2022-06-30 05:13:20 |
2 update references and layout
Amina Yu
 -88 word(s) 1137 2022-06-30 05:55:33 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Azman, K.F. Molecular Mechanisms of Brain-Derived Neurotrophic Factor. Encyclopedia. Available online: https://encyclopedia.pub/entry/24658 (accessed on 04 December 2024).
Azman KF. Molecular Mechanisms of Brain-Derived Neurotrophic Factor. Encyclopedia. Available at: https://encyclopedia.pub/entry/24658. Accessed December 04, 2024.
Azman, Khairunnuur Fairuz. "Molecular Mechanisms of Brain-Derived Neurotrophic Factor" Encyclopedia, https://encyclopedia.pub/entry/24658 (accessed December 04, 2024).
Azman, K.F. (2022, June 30). Molecular Mechanisms of Brain-Derived Neurotrophic Factor. In Encyclopedia. https://encyclopedia.pub/entry/24658
Azman, Khairunnuur Fairuz. "Molecular Mechanisms of Brain-Derived Neurotrophic Factor." Encyclopedia. Web. 30 June, 2022.
Molecular Mechanisms of Brain-Derived Neurotrophic Factor
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms23126827

Brain-derived neurotrophic factor (BDNF) has been extensively investigated, and it has emerged as an important regulator of synaptic plasticity, neuronal survival, and differentiation. In addition, BDNF serves as a crucial molecular target for the development of drugs to treat neurological diseases. The synthesis and maturation of BDNF is a multistep process, starting with the formation of several precursor isoforms. 

BDNF Molecular Mechanisms Signaling Cascades

1. Introduction

Neurodegenerative diseases are characterized by the gradual loss of neuronal structure or function, which can lead to neuronal death. Neurodegenerative disease often results in progressive cognitive, functional, and behavioral changes, manifested as dysfunctional motor and cognitive impairment. The most common types of neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), have all been extensively studied. Neurodegenerative diseases represent a major socioeconomic burden worldwide. The risk of acquiring a neurodegenerative disease increases dramatically with age [1]. Thus, with an aging population, the number of people affected is set to increase even further, necessitating the development of therapeutic strategies capable of reversing or stopping the degenerative process.
Neurotrophins are regulatory factors that mediate the differentiation and survival of neurons [2]. Neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4/5 (NT4/5), which are all derived from a common ancestral gene and have similar sequences and structures. Among neurotrophins, Brain-derived neurotrophic factor (BDNF) has been extensively investigated, and it has emerged as an important regulator of synaptic plasticity, neuronal survival, and differentiation. In addition, BDNF serves as a crucial molecular target for the development of drugs to treat neurological diseases. The first evidence of BDNF’s role in the etiology of neurodegenerative illnesses was discovered in the early 1990s. Since then, research on BDNF in neurodegenerative diseases has grown tremendously. 

2. BDNF Molecular Mechanisms and Signaling Cascades

The synthesis and maturation of BDNF is a multistep process, starting with the formation of several precursor isoforms. The precursor form of BDNF protein, preproBDNF, is synthesized in the endoplasmic reticulum (Figure 1) [3]. PreproBDNF is then converted into a precursor proneurotrophin isoform of BDNF (proBDNF) by the removal of the signal peptide. The proBDNF is made up of 129 amino acids with an N-terminal pro-domain and 118 amino acids, with a mature domain at the C-terminus [4]. The mature isoform of the BDNF (mBDNF) is produced by additional cleavage of the proBDNF. ProBDNF can be cleaved intracellularly by endoproteases from the subtilisin-kexin family, such as furin, or by convertases in intracellular vesicles [5]. Plasmin and matrix metalloproteases 2 and 9 (MMP2 and MMP9) are required for the extracellular cleavage of proBDNF [6]. The physiological activity of mBDNF and proBDNF is enabled by their secretion into the extracellular space. BDNF secretion can be either constitutive or activity-dependent, depending on the cell type [4]. In neuronal cells, both proBDNF and mBDNF are released upon cellular membrane depolarization [7]. The ratio of proBDNF to mBDNF varies, depending on the particular stages and regions of brain development. ProBDNF is higher in the early postnatal period, when it is important for the development of brain function, while mBDNF is higher in adulthood for brain function, such as neuroprotection and synaptic plasticity [8].
Ijms 23 06827 g001 550
Figure 1. BDNF molecular mechanisms and signaling cascades. The BDNF protein is synthesized as a precursor form, preproBDNF. PreproBDNF is then converted into proBDNF, which consists of a pro-domain and a mature domain. The proBDNF is further cleaved to generate the mature isoform, mBDNF. ProBDNF and mBDNF are exocytosed into the extracellular space. The pro-domain of the proBDNF binds to the sortilin receptor, while the mature domain binds to the p75NTR receptor and activates the JNK/cJUN, PI3K/AKT, and TRAF6/NF-kB signaling pathways, which determine neuronal fate. The mBDNF binds to the TrkB receptor and activates PLCs, PI3K, MAPK, and JAK/STAT signaling cascades, which promote CREB translation, neuronal survival, and synaptic plasticity.
The network of BDNF/tyrosine receptor kinase B (TrkB) and BDNF/ p75 pan-neurotrophin receptor (p75NTR) signaling pathways was first graphically mapped by Sandhya et al. in 2013. Briefly, the mature domain of proBDNF interacts preferentially with the p75NTR, while the pro-domain interacts with the sortilin receptor or other vacuolar protein-sorting 10 protein (Vps10p) [9]. The binding of proBDNF to its specific receptor activates signaling pathways that determine the fate of neurons and synapses. The proBDNF/p75NTR/sortilin binding complex can cause the activation of the c-Jun amino-terminal kinase (JNK) pathway, leading to dendritic spine loss, caspase release, and neuronal apoptosis [10]. The activation of JNK requires neurotrophin receptor-interacting MAGE homolog (NRAGE), neurotrophin receptor-interacting factor (NRIF), and tumor necrosis factor receptor-associated factor 6 (TRAF6). The binding of proBDNF to p75NTR can also cause the activation of the RhoA/Rho-associated kinase (ROCK) signaling pathway [11]. ROCK then activates the phosphatase and tension homolog (PTEN), which blocks the phosphoinositide 3-kinases-protein kinase B (PI3K/AKT) signaling necessary for TrkB-induced potentiation, thus eliciting apoptosis [12]. In addition, the TRAF6 signaling pathway is initiated, which leads to nuclear factor kappa B (NF-kB) activation. The activation of NF-kB can either promotes neuronal survival or nitric oxide production and neuroinflammation through multiple reactions [13].
On the other hand, mBDNF binds with the TrkB receptor, which has a high affinity. Upon BDNF binding, TrkB dimerizes, intracellular tyrosine residues are autophosphorylated, and several enzymes are activated, including phospholipase C (PLC), PI3K, guanosine triphosphate hydrolases (GTP), and Janus kinase (JAK) [14]. Through the activation of calcium-calmodulin-dependent protein kinase (CAMK) and protein kinase C (PKC), the PLC-dependent pathway leads to calcium-dependent signaling steps and the release of calcium ions from intracellular calcium storage, resulting in increased synaptic plasticity [15]. The PI3K/AKT-related pathway modulates N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity and exerts pro-survival and antiapoptotic activity [16]. The PI3K/Akt/mTOR cascade promotes dendritic growth and branching by regulating the synthesis of protein and the development of the cytoskeleton [17]. The mitogen-activated protein kinase (MAPK)/RAS-signaling cascade regulates the synthesis of protein during neuronal development and is also involved in the activation of extracellular-signal-regulated kinase 1/2 (ERK 1/2) and cAMP response element-binding protein (CREB) [18]. CREB activation leads to the initiation of transcription, the prolongation of synaptic potentiation, dendritic arborization, and neuroprotection [19]. The JAK/STAT pathway promotes major pelvic ganglia neurite outgrowths [20].
The specialized role of BDNF in the regulation of numerous physiological brain processes is determined by the interaction of BDNF isoforms with different types of receptors. For example, the activation of TrkB by BDNF is important in the late phase of long-term potentiation (L-LTP), which stimulates structural changes at the synapse [21]. On the other hand, P75NTR activation by proBDNF facilitates hippocampal long-term depression (LTD), which results in a decrease in synaptic strength [21]. The disruptions in BDNF production that result in signaling-cascade failure may be responsible for a range of neurological disorders. In addition, changes in BDNF levels and activities have been associated with a variety of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS.

References

  1. Hou, Y.; Dan, X.; Babbar, M.; Wei, Y.; Hasselbalch, S.G.; Croteau, D.L.; Bohr, V.A. Ageing as a Risk Factor for Neurodegen-erative Disease. Nat. Rev. Neurol. 2019, 15, 565–581.
  2. Dechant, G.; Neumann, H. Neurotrophins. Mol. Cell. Biol. Neuroprotection CNS 2003, 513, 303–334.
  3. Foltran, R.B.; Diaz, S.L. BDNF Isoforms: A Round Trip Ticket between Neurogenesis and Serotonin? J. Neurochem. 2016, 138, 204–221.
  4. Mowla, S.J.; Farhadi, H.F.; Pareek, S.; Atwal, J.K.; Morris, S.J.; Seidah, N.G.; Murphy, R.A. Biosynthesis and Post-translational Processing of the Precursor to Brain-derived Neurotrophic Factor. J. Biol. Chem. 2001, 276, 12660–12666.
  5. Je, H.S.; Yang, F.; Ji, Y.; Nagappan, G.; Hempstead, B.L.; Lu, B. Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses. Proc. Natl. Acad. Sci. USA 2012, 109, 15924–15929.
  6. Vafadari, B.; Salamian, A.; Kaczmarek, L. MMP-9 in Translation: From Molecule to Brain Physiology, Pathology, and Therapy. J. Neurochem. 2016, 139, 91–114.
  7. Dieni, S.; Matsumoto, T.; Dekkers, M.; Rauskolb, S.; Ionescu, M.S.; Deogracias, R.; Gundelfinger, E.D.; Kojima, M.; Nestel, S.; Frotscher, M.; et al. BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons. J. Cell Biol. 2012, 196, 775–788.
  8. Yang, J.-L.; Lin, Y.-T.; Chuang, P.-C.; Bohr, V.A.; Mattson, M.P. BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1. Neuromolecular Med. 2013, 16, 161–174.
  9. Deinhardt, K.; Chao, M.V. Shaping Neurons: Long and Short Range Effects of Mature and ProBDNF Signalling upon Neuronal Structure. Neuropharmacology 2014, 76, 603–609.
  10. Nykjaer, A.; Willnow, T.E. Sortilin: A receptor to regulate neuronal viability and function. Trends Neurosci. 2012, 35, 261–270.
  11. Simmons, D.A. Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington’s Disease. J. Huntington’s Dis. 2017, 6, 303–325.
  12. Song, W.; Volosin, M.; Cragnolini, A.B.; Hempstead, B.L.; Friedman, W.J. ProNGF Induces PTEN via p75NTR to Suppress Trk-Mediated Survival Signaling in Brain Neurons. J. Neurosci. 2010, 30, 15608–15615.
  13. Sandhya, V.K.; Raju, R.; Verma, R.; Advani, J.; Sharma, R.; Radhakrishnan, A.; Nanjappa, V.; Narayana, J.; Somani, B.L.; Mukherjee, K.K.; et al. A network map of BDNF/TRKB and BDNF/p75NTR signaling system. J. Cell Commun. Signal. 2013, 7, 301–307.
  14. Colucci-D’Amato, L.; Speranza, L.; Volpicelli, F. Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int. J. Mol. Sci. 2020, 21, 7777.
  15. Minichiello, L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 2009, 10, 850–860.
  16. Gonzalez, A.; Moya-Alvarado, G.; Gonzalez-Billaut, C.; Bronfman, F.C. Cellular and molecular mechanisms regulating neuronal growth by brain-derived neurotrophic factor. Cytoskeleton 2016, 73, 612–628.
  17. Jaworski, J.; Spangler, S.; Seeburg, D.P.; Hoogenraad, C.C.; Sheng, M. Control of Dendritic Arborization by the Phospho-inositide-3′-Kinase–Akt–Mammalian Target of Rapamycin Pathway. J. Neurosci. 2005, 25, 11300–11312.
  18. Panja, D.; Kenney, J.W.; D’Andrea, L.; Zalfa, F.; Vedeler, A.; Wibrand, K.; Fukunaga, R.; Bagni, C.; Proud, C.G.; Bramham, C.R. Two-Stage Translational Control of Dentate Gyrus LTP Consolidation Is Mediated by Sustained BDNF-TrkB Signaling to MNK. Cell Rep. 2014, 9, 1430–1445.
  19. Zhao, H.; Alam, A.; San, C.-Y.; Eguchi, S.; Chen, Q.; Lian, Q.; Ma, D. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Brain Res. 2017, 1665, 1–21.
  20. Lin, G.; Bella, A.J.; Lue, T.F.; Lin, C. Brain-Derived Neurotrophic Factor (BDNF) Acts Primarily via the JAK/STAT Pathway to Promote Neurite Growth in the Major Pelvic Ganglion of the Rat: Part 2. J. Sex. Med. 2006, 3, 821–829.
  21. Sakuragi, S.; Tominaga-Yoshino, K.; Ogura, A. Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity. Sci. Rep. 2013, 3, 3185.
More
©Text is available under the terms and conditions of the Creative Commons-Attribution ShareAlike (CC BY-SA) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Neurosciences
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Khairunnuur Fairuz Azman
View Times: 772
Revisions: 2 times (View History)
Update Date: 30 Jun 2022
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback