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

Author

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  • Agustin Anastasia

    (Weill Cornell Medical College of Cornell University)

  • Katrin Deinhardt

    (Skirball Institute, New York University School of Medicine
    Centre for Biological Sciences and Institute for Life Sciences, University of Southampton)

  • 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)

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.

Suggested Citation

  • Agustin Anastasia & Katrin Deinhardt & Moses V. Chao & Nathan E. Will & Krithi Irmady & Francis S. Lee & Barbara L. Hempstead & Clay Bracken, 2013. "Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction," Nature Communications, Nature, vol. 4(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3490
    DOI: 10.1038/ncomms3490
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    Cited by:

    1. Ruchi Lohia & Reza Salari & Grace Brannigan, 2019. "Sequence specificity despite intrinsic disorder: How a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein," PLOS Computational Biology, Public Library of Science, vol. 15(10), pages 1-29, October.

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