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

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in thebdnfgene, 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 BDNFMetis secreted in an activity-dependent manner. The nature of the cellular defect when both BDNFMetand 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 BDNFMeton BDNFValintracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNFMetoccurred only in neuronal and neurosecretory cells and that BDNFMetcould 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·BDNFMetheterodimers, 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 BDNFMetor the BDNFVal·BDNFMetheterodimer 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.