DEFINITION
Brain-derived neurotrophic factor, also known as BDNF, is a secreted protein that, in humans, is encoded by the BDNF. It is a member of the "neutrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF.
BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synaspses
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THE GENE
The BDNF gene is localized on the chromosome 11 (11p14.1).
In the following image from Entrez the locus is shown more in details
CHEMICAL STRUCTURE AND IMAGES
The primary structure of the pre-proBDNF as reported on GenBank is
| 1 | mtilfltmvi | syfgcmkaap | mkeanirgqg | glaypgvrth | gtlesvngpk | agsrgltsla |
| 61 | dtfehvieel | ldedqkvrpn | eennkdadly | tsrvmlssqv | pleppllfll | eeyknyldaa |
| 121 | nmsmrvrrhs | dparrgelsv | cdsisewvta | adkktavdms | ggtvtvlekv | pvskgqlkqy |
| 181 | yetkcnpmg | ytkegcrgid | krhwnsqcrt | tqsyvraltm | dskkrigwrf | iridtscvct |
| 241 | ltikrgr |
The highlighted sequence is referred to the mature BDNF (see below in SYNTHESIS AND TURNOVER)
The mature BDNF act as homodymer or heterodymer with neurotrophine-3 or neurotrophine-4/5. In the following image from PDBe there is the quaternary structure of the heterodymer BDNF/neurotrophine-4 (respectively in light blue and green)
Protein Aminoacids Percentage
The following graph is referred to pro-BDNF, the first product of translation
SYNTHESIS AND TURNOVER
Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters, 2007
Expression pattern
During development, BDNF protein expression is more abundant in the nervous system compared to other tissues and its levels are dramatically increased in the brain during postnatal development.
In the adult nervous system, BDNF displays a widespread distribution pattern, with the highest levels of mRNA and protein in the hippocampus, amygdala, cerebral cortex, and hypothalamus.
BDNF mRNA expression is mostly confined to neurons and there are only a few brain areas where BDNF mRNA is not detected and BDNF expression in adult tissues is detectable also outside of the central nervous system. Lower BDNF mRNA levels than in the hippocampus have been detected in the thymus, liver, spleen, heart, and lung.
mRNA synthesis
The Bdnf gene is comprised of at least eight distinct promoters that initiate transcription of multiple distinct mRNA transcripts, each of which contains an alternative 5′ exon spliced to a common 3′ coding exon that contains the entire open reading frame for the BDNF protein) Through the use of alternative promoters, splicing and polyadenylation sites, at least 18 transcripts can be produced, but remarkably, each encodes an identical initial BDNF protein product. The use of different promoters allows a tissue-specific regulation of BDNF expression.
Protein synthesis and post translational modifications
BDNF protein is synthesized as a precursor, pre-proBDNF protein, resulting after cleavage in a 32-kDa proBDNF protein. ProBDNF is either proteolytically cleaved intracellularly by enzymes like furin or pro-convertases and secreted as the 14 kDa mature BDNF (mBDNF), or secreted as proBDNF and then cleaved by extracellular proteases, such as metalloproteinases and plasmin, to mBDNF.
Nevertheless, both proBDNF and mBDNF are preferentially sorted and packaged into vesicles of the activity-regulated secretory pathway. ProBDNF is not an inactive precursor of BDNF, but rather it is a signalling protein in its own right. ProBDNF is released in the immature and mature CNS in an activity dependent manner.
pro BDNF has the N-terminal moiety rich in methionine
Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in Dicentrarchus labrax., 2010
Pro28Kda BDNF peptide is not further processed into the mature 14 kDa BDNF form but it represents a true final proteolytic product generated by a specific Ca2+-dependent serine proteinase known as Membrane-Bound Transcription Factor Site-1 protease (MBTFS-1; EC = 3.4.21.112, Alternative names: S1P endopeptidase, Site-1 protease) , also known as Subtilisin/kexin-isozyme 1 (SKI-1), while mature 14 KDa BDNF is generated intracellularly by furin, or extracellularly by plasmin and matrixmetalloprotease-7.
Furin and Plasmin release the N-terminal of BDNF which is methionine rich while they are methionine poor
CELLULAR FUNCTIONS
Cellular localization
BDNF is present in pre- and postsynaptic vescicles and it can undergo both retrograde and anterograde transport. Moreover, BDNF can act via autocrine and paracrine mechanisms, depending on the site of cell surface receptors through which it signals. The activity-regulated release of BDNF can occur via three mechanisms dependent on the site of release:
- Ca2+ influx-dependent release from postsynaptic sites, which is mediated by Ca2+influx through ionotropic glutamate receptors and voltage gated Ca2+-channels
- Ca2+ influx-dependent release from presynaptic sites
- Ca2+ influx-independent release that relies on Ca2+ release from intracellular stores
Biological function
A simple role for BDNF in learning and memory?, 2010
TrkB activation by BDNF follows the general scheme for receptor tyrosine kinases (dymerization and transphopsphorilation of Tyr residues) and initiates three major cascades of signalling pathways:
- phospholipase C γ (PLC γ)
- phosphatidylinositol 3-kinase (PI3K)
- extracellular signal-regulated kinases (ERK), member of the mitogen-activated protein kinase (MAPK)
EFFECT OF PLC γ PATHWAY
Activation of PLC γ pathway is directly implicated in a rise of intracellular Ca2+ via its release from intracellular stores, and in the activation of the Ca2+-calmodulin dependent kinase, CaMKII.
CaMKII :
- activates transcription factor CREB that recognize CRE and a CaRE regulatory elements in the Bdnf gene, activating its transcription. Thus, BDNF can regulate its own expression via activation of CaMKII signalling
- induces mRNA translation at postsynpatic sites
Another effect of PLC γ is the inibition of GABAergic transmission at postsynaptic sites
EFFECT OF PI3K PATHWAY
PI3K can be activated in different ways:
- directly by TRKB through the intermediation of Src, Grb2 and Gab1
- indirectly by RAS
The PI3K pathway was shown to mediate the protective effects of BDNF in several neuronal cell types in vitro, including hippocampal neurons.
It also facilitate local translation of proteins in dendrites by activation of mammalian target of rapamycin (mTOR)
EFFECT OR ERK/MAPK PATHWAY
TRKB recruits SH2 (src homology-type 2) linker proteins such as shc (src homology domain containing) and insulin receptor substrate-1 and -2). Src sequentially recruits an intermediary protein Grb2 and the guanine nucleotide exchange factor SOS, initiating the GTP loading and activation of Ras and the activation of the Raf, MEK and ERK kinase cascade.
This pathway transduces a pro-survival signaling
OTHER EFFECTS OF TRKB
In postsynaptic neurons BDNF potentiates glutammaergic transmission through
- the increase of NDMA receptors activity and Ca2+ influx through src-family tyrosine kinase Fyn
- the increase of AMPA receptors translocation to the cytoplasmic membrane
The association of BDNF with TrkB modulates or activates ion channels including Na+, Ca2+ and K+channels, within a range of seconds to minutes, through intracellular signalling cascades. So it can modulate neuronal excitability
BNDF binds also p75NTR at low affinity. It is preferentially binded by proBDNF which has distinct functional effect.
BDNF, Long Term Potentiation and Plasticity
LTP is the best studied form of synaptic plasticity and is considered as a cellular correlate of learning and memory. It is defined as an activity induced sustained increase in synaptic strength. The induction of LTP is associated with the activation of a large number of signalling cascades, including the ones activated by BDNF.
BDNF is essential for late phase LTP (L-LTP), which lasts at least 8 h after tetanization. L-LTP depends on both gene transcription and protein synthesis, and requires cAMP signalling and CREB.
The activity-driven and persistent increase in synaptic efficacy, the hallmark of LTP, is accompanied by ultrastructural changes in dendritic spines at excitatory glutamatergic synapses,.
These changes include the formation of new spines and increases in the number of glutamatergic AMPA receptors in the dendritic spines.
BDNF can increase the number of dendritic spines in CA1. Similarly BDNF overexpression increase dendritic complexity in hippocampal dentate gyrus.
Therefore BDNF modulates the number and shape of dendritic spines in mature hippocampal neurons.
REGULATION
Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons, 2008
BDNF splice variants from the second promoter cluster support cell survival of differentiated neuroblastoma upon cytotoxic stress, 2008
Regulation of transciption
It has been demonstrated that BDNF transcription from promoter IV is induced by neuronal activity. In fact animals whit a knock-in mutation on exon IV exhibit disrupted sensory experience-dependent induction of Bdnf expression
Protein non-coding antisense transcripts are expressed from the human BDNF gene locus. These may function as another level of complexity in the regulation of BDNF gene expression in vivo.
Regulation of mRNA trafficking
BDNF gene contain two poliadenylation sites that allow the prdouction of a short and a long 3′UTR mRNAs. Short 3’UTR Bdnf mRNA is restricted to the soma, whereas the long 3′UTR Bdnf mRNA is also targeted to dendrites for local translation (here it promotes dendritic spine remodeling in later postnatal development)
Regulation of signaling
The BDNF-TRKB signaling is regulated in different ways:
- TrkB splice variants lacking the tyrosine kinase act as a clearance receptors
- p75NTR binds both pro-BDNF and BDNF ad has different function of TRKB. Infact it is involved in Long Term Depression, the opposite of LTP.
Regulation of maturation of proBDNF to BDNF is another way used to regulate the BDNF signaling.
DIAGNOSTIC USE
A simple role for BDNF in learning and memory?, 2010
It has been identified in the human BDNF gene the SNPs Val66Met.
This SNP consists in the substitution of Met for Val at position 66 in the pro-region of BDNF which not only alters the trafficking, distribution and activity-dependent release of BDNF from neurons but also results in memory impairments in rodent models and in an increased susceptibility towards disorders such as depression, bipolar disorder and eating disorder in humans carrying the mutation
Potential therapeutic uses of BDNF in neurological and psychiatric disorders, 2011
BDNF AND Parkinson's Disease
It has been demonstrated that BDNF supports the survival of nigral dopaminergic neurons, and that expression of the BDNF protein and its mRNA is reduced in nigral neurons in Parkinson’s disease
In rodent models, BDNF treatment prevented the loss of dopaminergic neurons in the substantia nigra after 6 - hydroxydopamine or 1- methyl- 4 - phenylpyridinium (MPP)-induced lesion
Furthermore, BDNF protein infusion exhibited beneficial anatomical and behavioural effects in MPP-induced parkinsonism in non-human primates, by reducing cell loss and enhancing striatal reinnervation
BDNF and Alzheimer's Disease
BDNF levels become deficient in the entorhinal cortex and the hippocampus in Alzheimer’s disease.
Sustained BDNF gene delivery using viral vectors after disease onset resulted in elevated BDNF levels in the entorhinal cortex and, through anterograde transport, in the hippocampus
It also restored the expression of two-thirds of gene sets that were perturbed as a result of mutant APP expression in both the entorhinal cortex and the hippocampus, and learning and memory. However, BDNF treatment did not change amyloid plaque density in other studies which suggests that the therapeutic effects of BDNF occur independently of diect action on APP
BDNF and Huntington's Disease
BDNF levels decline in the striatum and the cerebral cortex of patients with Huntington’s disease. Interestingly, there is little BDNF mRNA in the striatum, but there are readily detectable quantities of BDNF protein that is anterogradely transported from the cortex in Huntington’s disease. BDNF transport from the cortex to the striatum is impaired.
Infusion of the BDNF protein into the striatum of HTT-mutant mice increases the survival of enkephalin-immunoreactive striatal neurons and improves motor function
Early raise of BDNF in hippocampus suggests induction of
posttranscriptional mechanisms by antidepressants, 2009
