title: Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction.
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.
authors.affiliation: Department of Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Agustin
authors.initials: A
authors.lastname: Anastasia
authors.forename: Katrin
authors.initials: K
authors.lastname: Deinhardt
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Will
authors.forename: Krithi
authors.initials: K
authors.lastname: Irmady
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.forename: Clay
authors.initials: C
authors.lastname: Bracken
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D004926:Escherichia coli / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020439:Growth Cones / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; C509461:SORCS2 protein, human; C579455:BDNF protein, human; D051057:Proto-Oncogene Proteins c-akt
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