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BDNF pro-peptide: physiological mechanisms and implications for depression

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Abstract

Most growth factors are synthesized as precursors and biologically active forms are generated by proteolytic cleavage of the pro-domain. However, the biological functions of pro-domains are ill-defined. New roles were recently reported for the pro-domain of brain-derived neurotrophic factor (BDNF), a well-known growth factor in the brain. Interestingly, the pro-domain of BDNF (BDNF pro-peptide) is localized at presynaptic termini, where it facilitates long-term depression (LTD) in hippocampal slices, implicating it as a novel synaptic modulator. BDNF binds its pro-peptide with high affinity in a pH-dependent manner and when bound to BDNF, the BDNF pro-peptide cannot facilitate hippocampal LTD, representing a new mechanism of regulation. The BDNF pro-peptide is present in human cerebrospinal fluid (CSF) and levels were significantly lower in patients with major depressive disorder (MDD) than in controls. Notably, male MDD patients exhibit significantly lower levels of CSF pro-peptide than females. These findings demonstrate that the BDNF pro-peptide is a biologically important synaptic modulator and is associated with MDD, particularly in males.

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Acknowledgements

We thank Dr. Haruko Kumanogoh for the preparation of Figure 1.

Funding

This work was supported by the Japan Science and Technology Agency “Core Research for Evolutional Science and Technology (CREST)” (T.M. and M.K).

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Authors and Affiliations

  1. Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka, 563-8577, Japan

    Masami Kojima, Konomi Matsui & Toshiyuki Mizui

  2. Graduate School of Frontier Biosciences, Osaka University, Suita, 565-0871, Japan

    Masami Kojima & Konomi Matsui

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  1. Masami Kojima
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  2. Konomi Matsui
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Correspondence to Masami Kojima.

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Kojima, M., Matsui, K. & Mizui, T. BDNF pro-peptide: physiological mechanisms and implications for depression. Cell Tissue Res 377, 73–79 (2019). https://doi.org/10.1007/s00441-019-03034-6

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