BDNF: New Views of an Old Player in Traumatic Brain Injury

Abstract

Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.

Keywords: BDNF; genetics; neurotrophin; traumatic brain injury.

Figure 1.

Synthesis of BDNF. Adapted from Kowiański and others (2018). The BDNF gene is transcribed to BDNF mRNA, which leaves the endoplasmic reticulum as pre-proBDNF. Pre-proBDNF is then cleaved into proBDNF, which is released or cleaved into mature BDNF (mBDNF). mBDNF activates the TrkB receptor to promote plasticity and recovery from injury. proBDNF interacts with the p75 receptor, causing neurodegeneration and cell death.

Figure 2.

BDNF pathways. Adapted from Jin and others (2019). The proBDNF/p75/sortilin complex leads to activation of the JNK, c-Jun, and p53 signaling pathways, thus promoting deleterious processes such as apoptosis and synaptic depression. The mBDNF/TrkB receptor complex triggers activation of multiple signaling pathways, including PI3K/Akt and PLC-γ, that ultimately activate CREB, which transcribes genes associated with neuronal development and maintenance. mBDNF = mature BDNF.

Figure 3.

Val66Met allele frequencies by population. The presence of the BDNF Met allele considerably varies across populations. The Met allele is reported to be >10 times more prevalent in East Asian populations (41.1%) as compared with African populations (4.3%). These differences in allelic frequencies may have a role in the availability of BDNF across populations. Met = methionine; Val = valine.