Brain-Derived Neurotrophic Factor (BDNF): Novel Insights into Regulation and Genetic Variation

Abstract

Since its discovery, brain-derived neurotrophic factor (BDNF) has spawned a literature that now spans 35 years of research. While all neurotrophins share considerable overlap in sequence homology and their processing, BDNF has become the most widely studied neurotrophin because of its broad roles in brain homeostasis, health, and disease. Although research on BDNF has produced thousands of articles, there remain numerous long-standing questions on aspects of BDNF molecular biology and signaling. Here we provide a comprehensive review, including both a historical narrative and a forward-looking perspective on advances in the actions of BDNF within the brain. We specifically review BDNF’s gene structure, peptide composition (including domains, posttranslational modifications and putative motif sites), mechanisms of transport, signaling pathway recruitment, and other recent developments including the functional effects of genetic variation and the discovery of a new BDNF prodomain ligand. This body of knowledge illustrates a highly conserved and complex role for BDNF within the brain, that promotes the idea that the neurotrophin biology of BDNF is diverse and that any disease involvement is likely to be equally multifarious.

Association between BDNF rs6265 polymorphisms and postoperative cognitive dysfunction in Chinese Han Population

“…Brain-derived neurotrophic factor is the most ubiquitous and intensively studied member of the neurotrophic factor family, and the human BDNF gene located on chromosome 11 P13-14 expresses at least three functional BDNF peptides (proBDNF, mBDNF, and the prodomain) that elicit independent biological effects (Notaras & Buuse, 2019).…”

The BDNF Val66Met Polymorphism Modulates Resilience of Neurological Functioning to Brain Ageing and Dementia: A Narrative Review

“…Specific genetic combinations, such as that of APOE and BDNF Val66Met, may further identify cognitively vulnerable people who may be particularly advised to consider how they can reduce their risk of dementia outside of the influence of ageing and genetic inheritance. Although not reported here, the BDNF Val66Met polymorphism has also been linked to a deleterious response to stress and trauma [120], which may play a role in cognition and subsequently dementia, given the relation between neurodegenerative changes and an abnormal stress response in AD [121].…”

Neurotrophin signalling in amygdala-dependent cued fear learning

“…As recently recognized, pro-neurotrophins, the cleaved pro-domain as well as mature neurotrophins exert distinct cellular functions (compare Brigadski et al, Kojima et al in this issue). Specifically, pro-neurotrophins interact with the p75 neurotrophin receptor (p75NTR) and often induce effects that oppose those of mature neurotrophins when binding to their cognate Trk receptors (for reviews, see Costa et al 2018;Sasi et al 2017;Zanin et al 2017;Gibon and Barker 2017;Notaras and van den Buuse 2018;Becker et al 2018;Von Bohlen und Halbach and Von Bohlen und Halbach 2018). In line with the role of p75NTR signalling in apoptosis during neuronal differentiation, p75NTR is widely expressed in the developing nervous system and is substantially downregulated in adulthood (Roux and Barker 2002;Underwood and Coulson 2008;Ibanez and Simi 2012;Foltran and Diaz 2016).…”