Journal Article

Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction

Irmady, Krithi, Will, Nathan E., Hempstead, Barbara L., Lee, Francis S., Anastasia, Agustin, Chao, Moses V., Deinhardt, Katrin, Bracken, Clay

2013

Overview

A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor ( BDNF ) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75 NTR and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology. The Val66Met single-nucleotide polymorphism in the BDNF gene is implicated in neuropsychiatric disorders. Anastasia et al. show that this polymorphism results in structural changes in the brain-derived neurotrophic factor prodomain, and growth cone retraction in the hippocampal neurons.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/726/649 / 631/378/1686 / 631/378/340 / Animals / Anxiety disorders / Brain / Brain-derived neurotrophic factor / Brain-Derived Neurotrophic Factor - genetics / Brain-Derived Neurotrophic Factor - metabolism / Brain-Derived Neurotrophic Factor - secretion / Embryo, Mammalian / Escherichia coli - genetics / Gene Expression Regulation, Developmental / Growth Cones - metabolism / Growth Cones - pathology / HEK293 Cells / Hippocampus - growth & development / Hippocampus - metabolism / Hippocampus - pathology / Humanities and Social Sciences / Humans / Kinases / Life sciences / Ligands / Magnetic Resonance Spectroscopy / Memory - physiology / Mice / Mice, Knockout / Morphology / multidisciplinary / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neurogenesis - genetics / NMR / Nuclear magnetic resonance / Polymorphism / Polymorphism, Single Nucleotide / Protein Structure, Secondary / Protein Structure, Tertiary / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Rats / Receptors, Cell Surface - genetics / Receptors, Cell Surface - metabolism / Receptors, Nerve Growth Factor - genetics / Receptors, Nerve Growth Factor - metabolism / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Science / Science (multidisciplinary)