BDNF pro-peptide: physiological mechanisms and implications for depression
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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.
KeywordsBDNF pro-peptide Proteolytic processing Long-term depression Synaptic modulator Major depressive disorder
We thank Dr. Haruko Kumanogoh for the preparation of Figure 1.
This work was supported by the Japan Science and Technology Agency “Core Research for Evolutional Science and Technology (CREST)” (T.M. and M.K).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24:4401–4411CrossRefGoogle Scholar
- Dwivedi Y, Rao JS, Rizavi HS, Kotowski J, Conley RR, Roberts RC, Tamminga CA, Pandey GN (2003) Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects. Arch Gen Psychiatry 60:273–282CrossRefGoogle Scholar
- Mizui T, Ishikawa Y, Kumanogoh H, Lume M, Matsumoto T, Hara T, Yamawaki S, Takahashi M, Shiosaka S, Itami C, Uegaki K, Saarma M, Kojima M (2015) BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc Natl Acad Sci U S A 112:E3067–E3074CrossRefGoogle Scholar
- Mizui T, Hattori K, Ishiwata S, Hidese S, Yoshida S, Kunugi H, Kojima M (2019) Cerebrospinal fluid BDNF pro-peptide levels in major depressive disorder and schizophrenia. J Psychiatr Res 113:190–198Google Scholar
- Roebroek AJ, Schalken JA, Bussemakers MJ, van Heerikhuizen H, Onnekink C, Debruyne FM, Bloemers HP, Van de Ven WJ (1986a) Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep 11:117–125CrossRefGoogle Scholar
- Slavik V, Dolezal T (2012) Cerebrospinal fluid : functions, composition, and disorders. Nova Biomedical BooksGoogle Scholar
- Smeekens SP, Steiner DF (1990) Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J Biol Chem 265:2997–3000Google Scholar
- Takahashi S, Nakagawa T, Kasai K, Banno T, Duguay SJ, Van de Ven WJ, Murakami K, Nakayama K (1995) A second mutant allele of furin in the processing-incompetent cell line, LoVo. Evidence for involvement of the homo B domain in autocatalytic activation. J Biol Chem 270:26565–26569CrossRefGoogle Scholar
- Uegaki K, Kumanogoh H, Mizui T, Hirokawa T, Ishikawa Y, Kojima M (2017) BDNF binds its pro-peptide with high affinity and the common Val66Met polymorphism attenuates the interaction. Int J Mol Sci 18(5)Google Scholar