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.

TitleVariant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.
Publication TypeJournal Article
Year of Publication2004
AuthorsChen Z-Y, Patel PD, Sant G, Meng C-X, Teng KK, Hempstead BL, Lee FS
JournalJ Neurosci
Volume24
Issue18
Pagination4401-11
Date Published2004 May 05
ISSN1529-2401
KeywordsAmino Acid Substitution, Animals, Brain-Derived Neurotrophic Factor, Cells, Cultured, Cercopithecus aethiops, Cerebral Cortex, COS Cells, Dimerization, Endothelial Cells, Gene Expression, Humans, Mice, Muscle, Smooth, Vascular, Mutation, Nerve Growth Factor, Neurons, Neurosecretory Systems, PC12 Cells, Polymorphism, Single Nucleotide, Protein Processing, Post-Translational, Protein Transport, Rats, Transfection
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 the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNF(Met)), 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 BDNF(Met) is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNF(Met) and wild-type BDNF (BDNF(Val)) 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 BDNF(Met) on BDNF(Val) intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF(Met) occurred only in neuronal and neurosecretory cells and that BDNF(Met) could alter the intracellular distribution and activity-dependent secretion of BDNF(Val). We determined that, when coexpressed in the same cell, approximately 70% of the variant BDNF forms BDNF(Val).BDNF(Met) 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 BDNF(Met) or the BDNF(Val).BDNF(Met) heterodimer compared with BDNF(Val). 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.

DOI10.1523/JNEUROSCI.0348-04.2004
Alternate JournalJ. Neurosci.
PubMed ID15128854
PubMed Central IDPMC6729450
Grant ListR01 NS030687 / NS / NINDS NIH HHS / United States
NS30687 / NS / NINDS NIH HHS / United States