Chapter Five - Releasing Mechanism of Neurotrophic Factors via Polysialic Acid
Introduction
Neurotrophic factors are soluble molecules that bind to specific receptors to regulate cell growth, survival, differentiation, and maintenance in the central nervous system (CNS) and peripheral nervous systems in an autocrine and/or paracrine manner. In 1951, nerve growth factor (NGF) was first identified in sarcoma tissues and was shown to cause the outgrowth of fibers from sensory nerves (Levi-Montalcini & Hamburger, 1951). Several other neurotrophic factors have since been characterized and classified into three groups based on their structural and functional properties: the neurotrophin family, transforming growth factor (TGF) family (glial cell line-derived neurotrophic factor (GDNF) family), and ciliary neurotrophic factor (CNTF) family (Fig. 1).
The neurotrophin family consists of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4, which are involved in various brain functions, including axon targeting, synapse maturation, and plasticity (Chao, 2003, Poo, 2001). The GDNF family is comprised of GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). GDNF was identified in the supernatant of a rat glioma cell line as a growth factor promoting the survival of embryonic dopaminergic neurons of the midbrain (Lin, Doherty, Lile, Bektesh, & Collins, 1993). Members of this group have structural similarity with respect to the position of seven cysteine residues that form a total of three intramolecular disulfide bonds. Members of the GDNF family share ~ 50% sequence similarity, whereas that among TGF-β family is ~ 20%, although GDNF shares profound conformational similarity with TGF-β2 and bone morphogenetic protein (BMP)-7 (Eigenbrot & Gerber, 1997). GDNF binds to GDNF family receptor-α (GFRα) or GFRα–RET to form a signaling complex, which then forms a dimer to initiate signal transduction (Chen et al., 2001, Naveilhan et al., 1998). The CNTF family consists of leukemia inhibitory factor (LIF), interleukin (IL)-6, and CNTF, which was shown to be involved in the survival of ciliary neurons from chick embryonic extracts (Adler, Landa, Manthorpe, & Varon, 1979) and several types of neurons and neural stem cells (Müller, Chakrapani, Schwegler, Hofmann, & Kirsch, 2009). All members of this family adopt the all α structural conformation and form homodimers to bind CNTFR, LIFR, or gp130, (Kass, 2011).
The functions of these neurotrophic molecules have been well studied and described in the literatures. In the present review, we focus on the mechanism of BDNF secretion, particularly on a newly identified secretion mechanism that mediated by a unique glycan, polysialic acid that modifies neural cell adhesion molecule, NCAM.
Section snippets
Biochemical Features of BDNF
BDNF is enriched in adult brains and was first isolated from pig brains. It was biochemically shown to have survival-promoting activity on dorsal root ganglion cells (Barde, Edgar, & Thoenen, 1982). BDNF is biosynthesized as a precursor protein, pre-proBDNF, which consists of 247 amino acid residues and is proteolytically cleaved to proBDNF (229 aa, 32 kDa). ProBDNF is further processed in secretory vesicles by proteases such as Furin in many tissue types and seven-membered proprotein convertase
Regions and Cellular Distribution of BDNF
The detection of BDNF mRNA is frequently used as an indicator of the cellular localization of BDNF protein (Conner, Lauterborn, Yan, Gall, & Varon, 1997). BDNF protein is released from the biosynthesizing cells as a primary site. The mRNA for BDNF has been detected all over the tissues in throughout the CNS, including the olfactory bulb, cerebral cortex, hippocampus, amygdala, thalamus, hypothalamus, and spinal cord, and other nonneuronal tissues, such as the salivary gland, skeletal muscle,
Extracellular Secretion of BDNF
Two types of secretion mechanisms for BDNF and proBDNF from secretory vesicles have been characterized: constitutive release mechanism (activity-independent manner) and regulatory release (activity-dependent manner) mechanism, which is activated in response to electrical activity (Edelmann et al., 2014, Lessmann and Brigadski, 2009). Unlike other neurotrophins, such as NGF and NT-3, which are mainly secreted via the constitutive pathway, the majority of BDNF appears to be secreted by the
Conclusion
BDNF is involved in a variety of brain functions that modify the behavior of animals. Once released from cells, BDNF must bind to its target receptors to activate the downstream signaling pathways. Therefore, to better understand the mechanism by which BDNF and other neurotrophic factors are released from cells, further studies of cell type, timing and affected pathways are critical. Recently, glycan-mediated storage of BDNF on the cell surface and glycosidase-mediated BDNF release has both
Acknowledgments
This research was supported in part by Grants-in-Aid for Scientific Research (C) (15K06995) (to C.S.), Scientific Research on Innovative Areas (No. 23110002, Deciphering sugar chain-based signals regulating integrative neural functions) (26110708) (to C.S.) from the Ministry of Education, Science, Sports and Culture, and DAIKO foundation (to C.S.).
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