- Brain-Derived Neurotrophic Factor in Suicide Pathophysiology

Abstract

Neurotrophins (NTs) are growth factors that are critical in regulating structural, synaptic, and morphological plasticity and in modulating the strength and number of synaptic connections and neurotransmission (Thoenen, 2000). In addition, the role of NTs in the adult central nervous system is important because they participate in the maintenance of neuronal functions, the structural integrity of neurons, and neurogenesis (Cooper et al., 1996), suggesting their biological role during the entire life span. NTs are homodimeric proteins and are categorized into four different classes: nerve growth factor, brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5. Most functions of NTs are mediated by the tropomycin receptor kinase (Trk) family of tyrosine kinase receptors. The interaction of NTs with the Trk receptors is specific: nerve growth factor binds with TrkA, BDNF and NT-4 both bind to TrkB, and NT-3 binds to TrkC with the highest affinity but can also bind and mediate its actions via TrkA and TrkB receptors. All NTs can bind to the pan75 NT receptor (p75NTR), which plays a role in NT transport, ligand-binding specificity, and Trk functioning (Barbacid, 1994, 1995; Lewin and Barde, 1996; Schweigreiter, 2006). In addition to the full-length TrkB receptor, several noncatalytic truncated TrkB isoforms have also been identified; these isoforms lack the signaling domain, preventing the induction of a signal transduction mechanism. Binding of an NT to the appropriate Trk receptor leads to the dimerization and transphosphorylation of tyrosine residues in the intracellular domain of the Trk receptors and subsequent activation of signaling pathways (Chao et al., 2006; Reichardt, 2006), leading to altered transcription of critical genes.The most widely distributed member of NT family is BDNF (Huang and Reichardt, 2001). The BDNF gene lies on chromosome 11p13 and encodes pro-BDNF, a precursor peptide of mature BDNF (Seidah et al., 1996). BDNF is translated as 30–35 kDa preproproteins consisting of a preprodomain, a prodomain, and a C-terminal mature NT domain. BDNF levels and its intracellular localization in neurons are regulated via several different mechanisms, including BDNF transcripts, messenger RNA (mRNA) and protein transport, and regulated cleavage of pro-BDNF to mature BDNF. The pro-BDNF is produced in the endoplasmic reticulum, which is accumulated in the trans-Golgi network via the Golgi apparatus. Pro-BDNF can be cleaved in the endoplasmic reticulum by furin or in the regulated secretary vesicles by proconvertase enzymes. Pro-BDNF binds to sortilin, an intracellular chaperone that binds to the prodomain of BDNF to traffic it to the regulated secretory pathway, in the Golgi apparatus. This facilitates the correct folding of the mature BDNF domain. The mature domain of BDNF binds to carboxypeptidase E, thereby sorting BDNF to the regulated secretary pathway (Lu et al., 2005). Pro-BDNF can also be processed by serine protease plasmin when pro-BDNF is in the extracellular milieu (Pang et al., 2004). A substitution of valine (Val) to methionine (Met) at codon 66 in the prodomain impairs this sorting of BDNF (Egan et al., 2003). The impact of a BDNF Val66Met polymorphism has been widely studied in relation to the clinical characteristics of suicidal behavior (Zai et al., 2011).