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

Agustin Anastasia, Katrin Deinhardt, Moses V. Chao, Nathan E. Will, Krithi Irmady, Francis S. Lee, Barbara L. Hempstead () and Clay Bracken ()
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Agustin Anastasia: Weill Cornell Medical College of Cornell University
Katrin Deinhardt: Skirball Institute, New York University School of Medicine
Moses V. Chao: Skirball Institute, New York University School of Medicine
Nathan E. Will: Weill Cornell Medical College of Cornell University
Krithi Irmady: Weill Cornell Medical College of Cornell University
Francis S. Lee: Weill Cornell Medical College of Cornell University
Barbara L. Hempstead: Weill Cornell Medical College of Cornell University
Clay Bracken: Weill Cornell Medical College of Cornell University

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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 p75NTR 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.

Date: 2013
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3490

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DOI: 10.1038/ncomms3490

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