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Background

Brain-derived neurotrophic factor, or BDNF for short, is a protein in humans that is expressed primarily in areas of the brain such as the hippocampus, basal forebrain, hypothalamus, brainstem, and spinal cord (Bathina & Das, 2015). It is also expressed in the lungs, heart, spleen, gastrointestinal tract, liver, fibroblasts, and vascular tissue (Bathina & Das, 2015). The protein is encoded by the BDNF gene located on human chromosome 11 (Binder & Scharfman, 2004). It belongs to the family of neurotrophins, which in general, are proteins that are important in neuronal survival, development, function, and brain plasticity. It was first expected to only be responsible for neurogenesis—the growth and development of new neurons within the central nervous system (Martinowich, 2007). However, it’s now widely believed that the main function is to regulate synaptic plasticity (Martinowich, 2007). Synaptic plasticity is induced during memory formation and is necessary for information storage, so BDNF is important in learning, memory, and higher thinking (Martin, Grimwood, & Morris, 2000). BDNF is synthesized in the endoplasmic reticulum (Bathina & Das, 2015). It then moves through the Golgi and trans-Golgi network and is cleaved by a protein convertase enzyme to form the biologically active form of the protein that gets sent into secretory vesicles (Bathina & Das, 2015). Vesicles bind to carboxypeptidase E, an enzyme responsible for the biosynthesis of the protein. Mice have been studied to examine when a disruption in this binding occurs. When there is a disruption in this binding, the ability for cells to sort BDNF greatly decreases. Mice that are born with this problem have significant neuron loss that results in problems affecting balance and coordination, breathing, hearing, and even death, suggesting the protein's role in normal neuronal development (Demetre, 2009). Many studies have linked BDNF with multiple neurological diseases. Some of these include depression, Alzheimer’s disease, Huntington’s disease, and multiple sclerosis. In neurodegenerative diseases, BDNF levels are decreased. In addition to its neurological effects, BDNF plays a large role in homeostasis, specifically energy intake and body weight. Studies have also shown that physical activity can increase levels of brain BDNF. The positive benefits that exercise has on brain health and function are primarily due to optimizing BDNF levels, particularly in the hippocampus (Phillips, 2017). Rodents exposed to physical activity five days a week for four weeks demonstrate an increase in BDNF synthesis and release (Phillips, 2017). In addition, exercise that includes endurance training induces the expression of muscle-derived proteins that upregulate BDNF expression.

Structure

Brain-derived neurotrophic factor is a relatively small protein, only 27.48 kDa, made of 119 amino acid residues (Protein Data Bank). The secondary structure of the protein is primarily beta-sheets with only a small number of alpha-helices (Protein Data Bank). The protein is a non-covalently linked heterodimer and has close structural homology to nerve growth factor (NGF) proteins (Binder & Scharfman, 2004). BDNF contains a cysteine knot motif, indicating its importance in neurogenesis. There are a few single-nucleotide polymorphisms (SNPs) of BDNF. The most commonly studied one is Val66Met and is exclusive to humans. This point mutation occurs at position 196 (or amino acid residue 66) and mutates a guanine to adenine. Upon transcription, this mutation causes an amino acid switch of valine to methionine. This polymorphism plays a role in destabilizing the mRNA transcript, leading to premature degradation (Baj et al., 2013). The protein that is able to be translated is not trafficked or secreted sufficiently. It can potentially alter protein-protein interactions, binding affinities, localisation, or conformational stability of the protein (Nociti, 2020). Those with this deficit show a decline in short-term episodic memory along with abnormal activity in the hippocampus (Martinowich, 2007). This mutation is also associated with major depressive disorder (Martinowich, 2007).

Functions

Structural highlights

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