New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

Abstract

Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer's disease, Huntington's disease, depression and schizophrenia.

Keywords: Brain-derived neurotrophic factor; Neurodegenerative disorders; Psychiatric disorders; Secretion; Transcription; Transport.

Figures

Figure 1

Schematic illustration of the activity-dependent regulators for Brain-derived neurotrophic factor gene transcription. A variety of transcriptional factors and regulators participate in the activity-induced transcription of BDNF. BDNF gene structure and Ca2+-dependent regulation in BDNF exon IV and epigenetic regulation at the exon IX promoter region are presented. We referred to the description by Zheng et al[38], also see[180]. BDNF: Brain-derived neurotrophic factor; CaRF: Calcium responsive factor; USF: Upstream stimulatory factors; BHLHB: Basic helix-loop-helix; CREB: Cyclic AMP-responsive element binding protein; NFκB: Nuclear factor-κB.

Figure 2

Schematic illustration of activity-dependent brain-derived neurotrophic factor secretion. A possible mechanism of intracellular Ca2+-dependent secretion of BDNF suggested in literature. Ca2+ influx through NMDA receptor/L-type VGCC and subsequent Ca2+ release of internal stores via ryanodine receptors are required for secretion. CaMKII, PKA, synaptotagmin IV, and CAPS2 also critically contribute to the membrane fusion process of BDNF-containing vesicles. VGCC: L-type voltage-gated calcium channels; CaMKII: calcium/calmodulin-dependent protein kinase II; PKA: protein kinase A; CAPS2: Ca2+-dependent activator protein for secretion 2; BDNF: Brain-derived neurotrophic factor.

Figure 3

Molecular mechanisms of phencyclidine-induced synaptic loss as a cellular model of schizophrenia. Phencyclidine decreased the number of synaptic sites in cultured cortical neurons through blockade of Ca2+ influx via NMDARs and resultant suppression of BDNF secretion. The impairment in BDNF secretion reduced TrkB activation and resulted in decreased synaptic connectivity[15]. BDNF: Brain-derived neurotrophic factor; NMDAR: N-methyl-D-aspartate receptors; PCP: Phencyclidine.