Leo Sher, M.D.

Just as we cannot step in the same river twice, we will never again see the world of neuroscience as we did before the scientific advancements of the past 2-3 decades. These developments have profoundly influenced all biomedical fields.

Brain-derived neurotrophic factor (BDNF) was discovered in the beginning of 1980s by Yves Barde, Hans Thoenen, and their colleagues (1). They succeeded in identifying and purifying a biological substance from the brain that they named BDNF.

Neurotrophic factors are homodimeric proteins known to have a wide range of roles in development and function of the nervous system (2-5). They promote neuronal survival, regulate many aspects of neuronal development and function, including synapse formation and synaptic plasticity. Mammalian neurotrophins include BDNF, nerve growth factor (NGF), neurotrophin (NT) 3, and NT 4/5 and continued to be a focus for research. The neurotrophins have similar structure, biochemical characteristics and bind to two types of receptors: tyrosine kinase receptors TrkA, TrkB, or TrkC, or a common low-affinity neurotrophin receptor p75 (p75NTR) that has no tyrosine kinase domain. The BDNF gene encodes a precursor peptide, proBDNF. BDNF is initially synthesized as a precursor protein (preproBDNF) in the endoplasmic reticulum. Following cleavage of the signal peptide, proBDNF is transported to the Golgi for sorting into either constitutive or regulated secretory vesicles. It has long been thought that only secreted mature BDNF is biologically active, and that proBDNF is exclusively localized intracellularly, serving as an inactive precursor. However, recent research observations suggest that proBDNF may also be biologically active. BDNF plays critical roles in the survival, maintenance, and growth of the brain and peripheral neurons. BDNF participates in use dependent plasticity mechanisms such as long-term potentiation, learning, and memory. BDNF is found in various tissues and cell types, not just in the brain.

In humans, a common single nucleotide polymorphism at nucleotide 196 within the 5’pro-BDNF sequence encodes a variant BDNF at codon 66 (Val66Met) (6). In human subjects, the met allele is associated with poorer episodic memory, abnormal hippocampal activation and lower hippocampal n-acetyl aspartate (NAA). Neurons transfected with met-BDNF-GFP (green fluorescence protein) shows lower depolarization-induced secretion. Also, met-BDNF-GFP fails to localize to secretory granules or synapses.

Of various neurotrophins, BDNF has attracted a great deal of interest because of its potential role in the pathophysiology of many neuropsychiatric disorders including depression, schizophrenia, obsessive-compulsive disorder, Alzheimer’s disease, Huntington’s disease, Rett syndrome, dementia, anorexia nervosa_, bulimia nervosa, traumatic brain injury, and suicidal behavior (7-11). Treatment approaches that enhance BDNF-related signaling may have the potential to restore neural connectivity and improve condition of patients suffering from neuropsychiatric disorders.

References

1. Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1(5):549-53.
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5. Pardon MC. Role of neurotrophic factors in behavioral processes: implications for the treatment of psychiatric and neurodegenerative disorders. Vitam Horm 2010;82:185-200.
6. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112(2):257-69.
7. Kaplan GB, Vasterling JJ, Vedak PC. Brain-derived neurotrophic factor in traumatic brain injury, post-traumatic stress disorder, and their comorbid conditions: role in pathogenesis and treatment. Behav Pharmacol 2010;21(5-6):427-37.
8. Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 2011;10(3):209-19.
9. Pardon MC. Role of neurotrophic factors in behavioral processes: implications for the treatment of psychiatric and neurodegenerative disorders. Vitam Horm 2010;82:185-200.
10. Sher L. Brain-derived neurotrophic factor and suicidal behavior. QJM 2011; 104(5): 455-458.
11. Sher L. The role of brain-derived neurotrophic factor in the pathophysiology of adolescent suicidal behavior. Int J Adolesc Med Health, in press.