Brain derived neurotrophic factor (BDNF) is an important neuronal regulator that facilitates growth and specialization of new neurons and synapses. It is part of a larger molecular family, called neurotrophins, sharing characteristics with the nerve-growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Similarly to other neurotrophins it can be found in the central and peripheral nervous system in mammals. In the current review first the genetic makeup of BDNF is discussed.
Genetic expression is followed by the protein structure. Third, the signaling pathways and cascades associated with BDNF are presented. Last, a brief discussion about the protein’s functions concludes the paper. Genetic makeup and gene expression The BDNF gene is responsible for the transcription and translation of the BDNF protein. The BDNF gene is found on chromosome 11p in humans. The rather complex genetic structure and regulation starts with the transcription of nine different promoters, each comprising one of 11 exons, resulting in 19 distinct transcripts. The main coding sequence of the gene however is located in exon 9). With 8 additional upstream exons, exon 9 regulates cell and tissue specific expression. The gene expression can be auto regulated by the CREB pathway, through the activation of the TrkB receptor. Furthermore, BDNF exon IV gene expression can also be increased through neuronal excitation activating the PI3K signaling cascades. The signaling cascades are discussed in a subsequent section of the paper. Once the transcription of 9 distinct mRNAs takes place, the mRNAs are translated in the ribosomes, amino acid chains and further folding provide the proteins’ structure. Important to note is that expression of either one of the nine transcripts will lead to the same BDNF precursor. Following the genetic transcription, the mature BDNF (mBDNF) protein is synthesized in three steps. The precursor, pre-proBDNF is producesd in the endoplasmic reticulum and after cleavage it becomes proBDNF (molecular weight ~30kDa) (Cuncha et al., 2009). The proBDNF moves through the Golgi apparatus and is either secreted as proBDNF or mature BDNF (mBDNF, M.W. ~14kDa). As it will be discussed in a later section of the paper, mBDNF and proBDN have distinct binding properties related to altered intra- and extracellular activity.
The mBDNF is very similar in its primary structure to the other neurotrophic molecules. It shares roughly half of its amino acid sequence with NT-3, NT-4 and NGF. On the one hand, mBDNF and NT-3 and NT-4 are 119 amino-acid residue polypeptides. On the other hand, NGF is shorter by one amino acid residue. As noted by Jones and Reichardt (1990), the large degree of similarity can be traced back to the evolution of the complex vertebrate nervous systems as no similar growth factor has been shown in invertebrates. The large amino acid chains are subsequently folded into predominantly beta-sheets and beta-turns, mediated by a sequence of antiparallel hydrogen bonds along the chain’s backbone. Overall, the BDNF molecule contains roughly 70% β-sheets, 20% β-turns and 5-10% random coil. There is a total absence of α-helices.
In addition, the mBDNF molecules contain about 20% less beta-sheets than NGF. The further folding of the secondary structure gives the protein’s tertiary stricture as it takes shape in three dimensional space. The hydrophilic parts of the beta sheet will organize towards the outer layers of the molecule, while the hydrophobic parts will gravitate towards the inside. In addition, intermolecular interactions lead to a formation a homodimer (i.e. two equal parts of subunits). Thus the quaternary protein structure of mBDNF is a non-covalently-1 linked homodimer. The dimer structure of the protein is likely to play an important role in the later dimerization process in the signaling cascades. Signaling Pathways Neurotrophins bind to two separate types of receptor families. The first receptor class, is the tyrosine kinase (Trk) family receptors. NGF binds, with high affinity to the TrkA receptor. NT-3 also binds to the same receptor in some cases, though with lower affinity compared to NGF. mBDNF as well as NT-4 binds with high affinity to the TrkB receptor. Lastly, NT-3 binds with high affinity to the TrKC receptor. Once mBDNF binds to the TrkB receptor, it initiates dimerization of autophosphorylates which yield docking sites for different molecules.
Depending on which molecule binds to the docking sites, three types of signaling cascades might follow. First, the phospholipase C-γ (PLC- γ) pathway can be initiated by the docking of the PLC-γ molecule inside the membrane. In turn, PLC-γ acts as a catalyst to breaking down lipids in 1,3,5 triphosphate (IP3), leading to intracellular chain reactions, promoting a continuous release of Ca2+. The increased concentration of Ca2+ within the cell increases Ca mediated mRNA translation at post-synaptic sides. Also, it activates the CAMK-II kinase which binds to the CREB transcription factor that promotes BDNF gene transcription. Hence, BDNF is able to auto-regulate its gene expression. The phosphatidylinositol-3 kinase (PIK3/AKT) cascade can be activated if the Shc/grb2 complex binds to the docking site of the TrkB receptor. In addition to the Shc complex binder activation, the PIK3/AKT pathway can also be activated by the RAS pathway. The PI3K downstream cascade activates the CREB transcription factor. In addition to the promotion of gene transcription, the PI3K pathway also mediates protection of neurons in the hippocampus. Similarly, it has been shown by Vaillant and colleagues (1999) that the inhibition of the pathway can lead to reduced survival of neurons. The RAS/MAP (i.e. mitogen activated protein) cascade can also be activated by the SH2 intermediary protein followed by the Raf, MEK, ERK kinase cascade. The RAS pathway also facilitates neuron survival. The different pathways and cascade activation patterns are expected to depend on the different cell types and the pathological/physiological stimuli.
The second receptor that neurotrophins bind to is p75-neurotrophin (p75NTR) receptor. Trk and p75NTR are located very close to one another on the cell membrane. The receptor responds to NT-3, NT-4, NGF and BDNF. However, evidence suggests that proBDNF binds with higher affinity to p75NTR than to Trk receptor types. The binding of proBDNF to the p75NTR receptor activates two distinct signaling cascades. The JNK cascade (c-Jun N-terminal kinase), seems to play a role in apoptosis while the NF-KB cascade (Nuclear factor-B) promotes cell survival.
The activation and release of BDNF is important in aiding nerve cell support. Furthermore, it encourages the growth and specialization of new nerves (neurogenesis) and synapses (synaptogenesis). It is mostly active in learning and memory related brain areas, such as the hippocampus, the basal forebrain and the cortex. Recent studies have demonstrated that BDNF, in vivo, facilitates neuronal differentiation rather than neuronal survival. BDNF reduction in the brain does not result in significantly decreased neuron number but rather a decrease in dendritic complexity and density. In addition to neuronal differentiation, it also plays an important role in long-term potentiation (LTP). Even minor decrease or change in BDNF levels in rat brains can lead to impaired memory formation, learning, anxiety and aggression. In humans, an impaired function of the TrkB pathway can lead to similar effects. In addition to the impairments, BDNF was also linked to certain condition including schizophrenia, depression, OCD, Alzheimer’s disease and Huntington’s disease. However, experiments trying to administer BDNF exogenously, did not find significant improvements in any of the conditions. Yet, new research directions focus on increasing BDNF levels by leveling BNDF production and targeting the specific signaling pathways by the use of substances that mimic BDNF.
To conclude, BDNF is one of the essential molecules that promote cell survival, differentiation and neurogenesis. It also plays a crucial role in learning and memory, mediated by high activity in the hippocampus and the cortex. However, the protein’s activity has also been linked to various psychological and psychiatric conditions. Its complex genetic makeup and complex signaling pathways have been widely analyzed and well understood. Current research is needed in aiding understanding in BDNF’s role in the psychological and psychiatric conditions.
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