Dysfunction in Brain-Derived Neurotrophic Factor Signaling Pathway and Susceptibility to Schizophrenia, Parkinson's and Alzheimer's Diseases

Abstract

Brain-Derived Neurotrophic Factor (BDNF) is a dominant neurotrophic factor in the brain which plays a crucial role in differentiation, regeneration and plasticity mechanisms. Binding of the BDNF to its high-affinity Tropomyosin-related kinase B (TrkB) receptor leads to phosphorylation of TrkB, thus activating the three important downstream intracellular signaling cascades within the neural cells including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Phospholipase C-γ (PLCγ), and mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathways. Transcription of these pathways is regulated by cAMP Response Element-Binding protein (CREB) transcription factor, which can upregulate gene expression. In this review, we attempted to explore the role of BDNF and its associated pathways in susceptibility to Schizophrenia (Scz), Alzheimer's (AD), and Parkinson's (PD) diseases. Furthermore, we discuss dysfunction in BDNF signaling pathway and the therapeutic potential of BDNF in the treatment of these disorders. The review covers various therapeutic strategies including BDNF gene therapy, transplantation of BDNFexpressing cell grafts, epigenetic manipulation, and intraparenchymal BDNF protein infusion as well. This review seeks to achieve these goals by reviewing recent studies on BDNF and examining the details of BDNF pathway in any of the above-mentioned diseases.

Keywords: BDNF; Gene delivery; MAPK/ERK; PI3K/AKT; PLCγ; Susceptibility..