Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons

By Zhe-Yu Chen, P. Patel, Gayatree Sant, Chui-Xiang Meng, K. Teng, B. Hempstead, F. Lee. Journal of Neuroscience, 2004

900 citations recorded by the source corpus.

Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNFMet), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNFMet is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNFMet and wild-type BDNF (BDNFVal) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNFMet on BDNFVal intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNFMet occurred only in neuronal and neurosecretory cells and that BDNFMet could alter the intracellular distribution and activity-dependent secretion of BDNFVal. We determined that, when coexpressed in the same cell, ∼70% of the variant BDNF forms BDNFVal·BDNFMet heterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNFMet or the BDNFVal·BDNFMet heterodimer compared with BDNFVal. Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Developmental Neuroscience

View Paper: https://www.semanticscholar.org/paper/3a03016b6437d5b67f84f8ce17d1783f1809668b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Cognitive Neuroscience

In Developmental Neuroscience

Citations in the corpus

Activation of p75NTR by proBDNF facilitates hippocampal long-term depression (2005, background): “and accounts for a substantial proportion of total BDNF secreted extracellularl”
ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin (2005, background): “Proneurotrophins, including the precursor of BDNF (proBDNF), may be secreted from cells (Heymach and Shooter, 1995; Lee et al., 2001; Mowla et al., 2001; Chen et al., 2004) or cleaved intracellularly by furin or proconvertases to yield C-terminal mature neurotrophin dimers.”
BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity (2017, background): “This has been postulated to be responsible for altered spatial conformation, changed intracellular sorting and trafficking, as well as impaired release of neurotrophin into the synaptic cleft (Anastasia et al. 2013; Chen et al. 2004, 2005).”
The Brain-Derived Neurotrophic Factor val66met Polymorphism and Variation in Human Cortical Morphology (2004, positive): “A common polymorphism in the BDNF gene (val66met) in the 5 signal domain has been shown to affect intracellular packaging and regulated secretion of BDNF (Egan et al., 2003; Chen et al., 2004) and also human hippocampal function and episodic memory (Egan et al.”
Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. (2007, background): “To test this hypothesis, we examined the consequence of a naturally occurring human single-nucleotide polymorphism (SNP) in the BDNF prodomain (G196A, Val66Met), which impairs activity-dependent BDNF secretion (Chen et al., 2004; Egan et al., 2003).”