Explore the Features of Brain-Derived Neurotrophic Factor in Mood Disorders

Abstract

ObjectivesBrain-derived neurotrophic factor (BDNF) plays important roles in neuronal survival and differentiation; however, the effects of BDNF on mood disorders remain unclear. We investigated BDNF from the perspective of various aspects of systems biology, including its molecular evolution, genomic studies, protein functions, and pathway analysis.MethodsWe conducted analyses examining sequences, multiple alignments, phylogenetic trees and positive selection across 12 species and several human populations. We summarized the results of previous genomic and functional studies of pro-BDNF and mature-BDNF (m-BDNF) found in a literature review. We identified proteins that interact with BDNF and performed pathway-based analysis using large genome-wide association (GWA) datasets obtained for mood disorders.ResultsBDNF is encoded by a highly conserved gene. The chordate BDNF genes exhibit an average of 75% identity with the human gene, while vertebrate orthologues are 85.9%-100% identical to human BDNF. No signs of recent positive selection were found. Associations between BDNF and mood disorders were not significant in most of the genomic studies (e.g., linkage, association, gene expression, GWA), while relationships between serum/plasma BDNF level and mood disorders were consistently reported. Pro-BDNF is important in the response to stress; the literature review suggests the necessity of studying both pro- and m-BDNF with regard to mood disorders. In addition to conventional pathway analysis, we further considered proteins that interact with BDNF (I-Genes) and identified several biological pathways involved with BDNF or I-Genes to be significantly associated with mood disorders.ConclusionsSystematically examining the features and biological pathways of BDNF may provide opportunities to deepen our understanding of the mechanisms underlying mood disorders.

BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity

“…The conservative structure of BDNF, with 85.9–100 % identity among genes of various vertebrates and humans, determines its physiological function, to a large extent independently of the stage of phylogenetic development (Yeh et al. 2015 ). BDNF is a member of the neurotrophin family, which also includes nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) (Hohn et al.…”

Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway

“…Like other neurotrophins, a pro-BDNF was cleaved to a mature-BDNF (m-BDNF) in the endoplasmic reticulum or in other way, pro-BDNF is released into the extracellular environment and cleaved by plasmin (Barker 2009). Some studies have demonstrated that the pro-BDNF and the m-BDNF had opposite biological potentials (Barker 2009;Yeh et al 2015), while other studies indicated that pro-BDNF and m-BDNF collaborated with each other in the neurodegenerative diseases (Fahnestock et al 2002).…”

Can a systems approach produce a better understanding of mood disorders?

“…Studies examining the linkage of BDNF with bipolar disorder have reported both positive [66,67] and negative findings [68,69], meaning its importance is open to question. Yeh, Kao and Kuo used a range of computational approaches to marry GWAS with the known BDNF activity network [70]. They concluded that no significant association was observed between BDNF and affective disorders in the majority of genomic studies, although a consistent relationship between plasma/serum BDNF and affective disorders was reported.…”

“…and NOS3, and a clear association between their biological networks and affective disorders emerged [70]. Hence, by using a systems approach to expand a query from a single protein to several hundred interacting proteins (the interactome), novel biological insights were gained.…”

“…This could be addressed by either further clinical studies, or the use of systems approaches such as the interactome analysis of Yeh, Kao and Kuo described above [70]. These would further extend the biological coverage of the genomic analysis, improving the robustness of the 'disorder unique' or 'common between disorders' call for the identified biological hubs.…”