Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain-Derived Neurotrophic Factor / genetics*
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Brain-Derived Neurotrophic Factor / metabolism
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Embryo, Mammalian
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Escherichia coli / genetics
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Gene Expression Regulation, Developmental
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Growth Cones / metabolism*
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Growth Cones / pathology
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HEK293 Cells
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Hippocampus / growth & development
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Hippocampus / metabolism*
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Hippocampus / pathology
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Humans
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Magnetic Resonance Spectroscopy
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Memory / physiology
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurogenesis / genetics
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Polymorphism, Single Nucleotide*
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Nerve Growth Factor / genetics
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Receptors, Nerve Growth Factor / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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NGFR protein, human
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Nerve Tissue Proteins
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Receptors, Cell Surface
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Receptors, Nerve Growth Factor
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Recombinant Proteins
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SORCS2 protein, human
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BDNF protein, human
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Proto-Oncogene Proteins c-akt