BRAIN DERIVED NEUROTROPHIC FACTOR, HUMAN

Discovery

Barde et al. described the presence of a factor in a glioma-conditioned medium that supported the survival of embryonic sensory neurons and could be distinguished from nerve growth factor by immunological and functional criteria. Furthermore, it was demonstrated that the mammalian brain contained an activity similar to that of the glioma-conditioned medium. Then, Barde et al. purified a neuronal survival factor from the pig brain, and identified it as BDNF, the second member of the neurotrophin family.

Structure

BDNF is a polypeptide consisting of 119 aa residues. The human BDNF gene encodes a preproprotein of 247 aa residues (preproBDNF) . After cleavage, mature BDNF dimerizes through noncovalent interaction. BDNF has been identified in mammals, birds, reptiles, amphibians, and teleosts. Mammalian BDNF shows 100% homology. Six cysteines involved in the intramolecular disulfide bond are conserved among all vertebrate BDNFs.

Properties

Mr. 25,766 (mammalian preproBDNF); 12,300 (mammalian mature BDNF). pI ≧ 10.1. BDNF is soluble in water. Disulfide bridges are formed between Cys13 and Cys80, between Cys58 and Cys109, and between Cys68 and Cys111 (in mammalian mature BDNFs).

Gene, mRNA, and precursor

The human proBDNF gene, BDNF, location 11p14.1, consists of 12 exons. Human BDNF mRNA has 3827 bases that encode a preproBDNF of 247 aa residues. ProBDNF shows biased expression in the brain (RPKM 3.0), the lung (RPKM 1.2), and 11 other tissues, including the placenta and prostate. In the brain, higher levels of expression are observed in the hippocampus, cerebellum, and cerebral cortex.

Synthesis and release

BDNF mRNA levels are increased by development and neuronal activity. BDNF release is also stimulated by neuronal activity. BDNF is localized in a dense-core vesicle in dendrites of the hippocampal neurons, suggesting that BDNF release is a type of regulated release.

Receptors

BDNF binds to at least two classes of receptors: tropomyosin receptor kinase B (TrkB), the high-affinity receptor, and p75NTR, the low affinity receptor. Both TrkB and p75NTR are single-transmembrane receptors. The human NTRK2 gene encodes TrkB (Trk2) of 838 aa residues. The human NGFR gene encodes p75NTR of 427 aa residues. TrkB has a tyrosine-kinase domain in the cytoplasmic region. There are two truncated isoforms lacking the tyrosine-kinase domain.12 p75NTR has no tyrosine-kinase domain. The binding activities of mature BDNF are Kd=10 pM (TrkB) and 1 nM (p75NTR).

Agonists and Antagonists

BDNF, NT-3, NT-4, LM22A-4 (a synthetic, selective partial agonist for TrkB), and HIOC (a selective agonist for TrkB). ANA-12 (a selective, small-molecule noncompetitive antagonist for TrrkB), and Cyclotraxin B (a selective, noncompetitive antagonist or negative allosteric modulator for TrkB).

Biological functions

TrkB is expressed in the central and peripheral nervous systems. A higher level of expression is seen, especially in the hippocampus, cerebellum, and cerebral cortex. The activation of TrkB induces the survival of neurons, promotes the development of neuronal circuits, and induces synaptic plasticity. The function of p75NTR is less clear.

Clinical implications

The expression level of BDNF is decreased in the entorhinal cortex of Alzheimer’s disease patients. Val66Met mutation results in a reduction of hippocampal tissue. The mutation is reported in patients with learning and memory disorders, anxiety disorders, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Recently, it has been suggested that the modification of BDNF-TrkB signaling could provide a potential therapeutic strategy for neurodegenerative diseases and neuropsychiatric disorders, including epilepsy.

Description

Brain-derived neurotrophic factor is the second member of the neurotrophin-family trophic factors. BDNF is a polypeptide consisting of 119 amino acid residues, and forms a homodimer. There are two types of receptors binding to BDNF: tropomyosin receptor kinase B (TrkB), the high-affinity receptor, and p75NTR, the low affinity receptor. BDNF regulates the growth, maintenance, and survival of certain target neurons as well as the synaptic plasticity, learning, and memory through the activation of TrkB. On the other hand, the role of p75NTR is less clear.

Uses

Brain-derived neurotrophic factor (BDNF) recombinant human protein has been used as a supplement in various types of culture media.

General Description

The gene BDNF (brain derived neurotrophic factor) is mapped to human chromosome 11p14.1. BDNF is a member of the neurotrophin family of growth factors. The gene encodes a precursor protein, proBDNF. Mature BDNF (mBDNF) is synthesized by post-translational cleavage of proBDNF. Both proBDNF and mBDNF play crucial roles in cellular signaling. BDNF is expressed as the C-terminal portion of a 247 amino acid polypeptide precursor, which also contains a signal sequence of 18 amino acid residue and a propeptide of 110 amino acid residues. Recombinant human BDNF is a 27.0kDa homodimer of two 119 amino acid subunits linked by strong noncovalent interactions.

Biochem/physiol Actions

Like other members of this family, BDNF (brain derived neurotrophic factor) supports neuron proliferation and survival. BDNF can bind to a low affinity cell surface receptor called LNGFR (low-affinity nerve growth factor receptor), which also binds other neurotrophins such as NGF (nerve growth factor), NT-3 (neurotrophin-3) and NT-4. However, BDNF mediates its neurotrophic properties by signaling through a high affinity cell surface receptor called gp145/trkB (tropomyosin-related kinase B). BDNF also plays an important role in vascular function and participates in angiogenesis. It is involved in the pathogenesis of Alzheimer′s disease. ProBDNF interacts with p75 neurotrophin receptor, leading to long-term depression in the hippocampus.

storage

-20°C