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BDNF

[Brain-derived neurotrophic factor]

SOURCES

BDNF is found in neurons of the central nervous system. It is expressed predominantly in hippocampus, cortex, and synapses of the basal forebrain. The synthesis of BDNF is subject to regulation by neuronal activity and specific transmitter systems. BDNF expression is also switched on in Schwann cells following peripheral nerve lesion. BDNF is expressed also in muscles and its expression is upregulated in denervated muscles.

PROTEIN CHARACTERISTICS

BDNF is a basic protein (pI = 9.99) of 252 amino acids that is synthesized as a precursor with a 18 amino acid hydrophobic signal sequence and a prosequence of 112 amino acids. The proteins isolated from various mammalian sources are almost identical in their sequences and also display a conserved tissue distribution.

Some protein domains of BDNF are identical with those of NGF and another neurotrophic factor, designated NT-3 (neurotrophin-3) (see also: Neurotrophins). Polyclonal antibodies raised against murine NGF have been shown to cross-react with both other proteins. They also totally or partially block the bioactivities of the other proteins. At the protein level these three proteins show 50 % total homology (see also: gene family). The variable domains are believed to control the specificity of expression in certain types of neurons.

GENE STRUCTURE

The human BDNF gene is located on chromosome 11p15.5-p11.2 between the loci FSHB and HVBS1 (which covers a region of approximately 4 Mb). The murine gene is located on chromosome 2.

The rat BDNF gene contains four 5' exons that are linked to separate promoters and one 3' exon encoding the BDNF protein. Timmusk et al (1995) have analyzed the relative importance of the regulatory regions in vivo by generating transgenic mice with different promoter constructs of the BDNF gene.

RECEPTORS

The biological activity of BDNF is mediated by a receptor that belongs to the trk family of receptors encoding a tyrosine-specific protein kinase. BDNF only binds weakly to the gp140trk receptor (to which NGF binds with high affinity), and it binds to the NGF receptor known as LNGFR (see: NGF). It has been possible, by combination of structural elements from NGF, BDNF and NT-3, to engineer the multifunctional Pan-Neurotrophin-1 (see also: Neurotrophins, Muteins) that efficiently activates all trk receptors and displays multiple neurotrophic specificities.

BIOLOGICAL ACTIVITIES

BDNF selectively supports the survival of primary sensory neurons and retinal ganglia. The factor supports survival and differentiation of certain cholinergic neurons and also some dopaminergic neurons in vitro. BDNF has been shown recently to prevent death of cultured embryonic rat spinal motor neurons at picomolar concentrations and to rescue substantial numbers of motor neurons that would otherwise die after lesioning of the neonatal sciatic or facial nerve. BDNF inhibits the normal cell death of embryonic chick motor neurons.

BDNF does not appear to act on sympathetic ganglia. In specific neurons of the central nervous system located in the hippocampus and the cortex the synthesis of BDNF is influenced by neuronal activity either positively (glutamate transmitter system) or negatively (GABA transmitter system).

BDNF has been shown to rapidly potentiate the spontaneous and impulse-evoked synaptic activity of developing neuromuscular synapses in culture and thus appears to be involved in the regulation of functions of developing synapses.

Some neurons, including trigeminal sensory neurons and cerebellar neurons appear to switch their dependence from BDNF to NGF and NT-3, respectively. BDNF can act also via an autocrine mode since many hippocampal and cortical neurons coexpress BDNF and the trkB receptor. BDNF also acts in concert with other factors and neurotrophins. The biological activities of BDNF and NT-3 (neurotrophin-3) are additive, and BDNF also interacts with LIF.

The tissue distributions and also the neuronal specificities of BDNF, NGF and NT-3 differ markedly from each other. BDNF, and also NT-3 act on some cells that do not respond to NGF. It has been possible to create chimaeric proteins consisting of various BDNF and NGF domains and these hybrid proteins have been found to show simultaneously some of the activities of either factor (see also: Muteins).

Glucocorticoid hormones, which are important regulators of brain development and aging and which can impair the capacity of hippocampal neurons to survive various neurological insults have been shown to prevent activity-dependent increases of BDNF mRNA in cultures of rat hippocampal neurons. It has been suggested, therefore, that the known ability of glucocorticoids to exacerbate neuronal injury following ischemia and other metabolic insults may be due to antagonism of regulatory mechanisms governing levels of BDNF and other Neurotrophins in the brain.

TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES

The biological consequences of a BDNF gene disruption have been studied in transgenic knock-out mice generated from ES cells carrying a targeted deletion of the gene.

Mice homozygous for a targeted disruption of the BDNF gene generally die within 2 days after birth although some of these animals live for 2-4 weeks. These animals develop symptoms of nervous system dysfunction, including ataxia. BDNF deficient mice have substantially reduced numbers of cranial and spinal sensory neurons. Although their central nervous systems show no gross structural abnormalities, expression of neuropeptide Y and calcium-binding proteins is altered in many neurons, suggesting that BDNF is essential for normal differentiation of the central nervous system. These animals do not have obvious deficits in motor neuron populations (see also: trk for information of transgenic mice lacking a function BDNF receptor).

Transgenic mice lacking BDNF expression show an 80 % reduction in neurons of the vestibular ganglion that innervate the inner ear organs responsible for proper balance and locomotion. The few remaining vestibular axons fail to contact the vestibular sensory epithelia. They terminate in the adjacent connective tissue. Survival of sympathetic, midbrain dopaminergic and motor neurons is not affected. The animals also show a 25-44 % reduction in trigeminal neurons that connect the hindbrain with whisker pads and other facial cutaneous targets and a 55-65 % reduction in neurons of the nodose and petrosal ganglia which relay information from the heart, major vessels, lung, and gut to the brain stem. In addition the number of mechanoreceptor neurons in the dorsal root ganglion is reduced also.

DETECTION AND ASSAY METHODS

Specific ELISA assays are available. The bioactivity of BDNF can be monitored by a survival assay of embryonic chicken sensory and sympathetic neurons.

For further information on assays for cytokines see also: bioassays, cytokine assays.

CLINICAL USE AND SIGNIFICANCE

Since BDNF supports the survival of sensory neurons, retinal ganglion cells, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons in vitro it may be of use in local treatment of nerve degeneration disorders such as Parkinson's disease. The effects of BDNF on motor neurons raise the possibility that it may be useful in treating patients with motor neuropathies and amyotrophic lateral sclerosis.

BDNF infusion into the adult normal rat hippocampus, cortex, and striatum has been shown to increase neuropeptide Y expression in all three regions and to increase expression of other neuropeptides by hippocampal and cortical neurons.



 

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