BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia

• Main Authors: Zhengrong Zhang, Jing Huang, Yong Shen, Rena Li
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-09-01
• Series: Frontiers in Molecular Neuroscience
• Subjects: schizophrenia; β-secretase (BACE1); neuregulin-1 (NRG1); erb-b2 receptor tyrosine kinase 4 (ErbB4); signaling pathway
• Online Access: http://journal.frontiersin.org/article/10.3389/fnmol.2017.00302/full

Schizophrenia is a chronic psychiatric disorder with a lifetime prevalence of about 1% in the general population. Recent studies have shown that Neuregulin-1 (Nrg1) is a candidate gene for schizophrenia. At least 15 alternative splicing of NRG1 isoforms all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for Nrg1 biological activity including the formation of myelin sheaths and the regulation of synaptic plasticity. It is known that Nrg1 can be cleaved by β-secretase (BACE1) and the resulting N-terminal fragment (Nrg1-ntf) binds to receptor tyrosine kinase ErbB4, which activates Nrg1/ErbB4 signaling. While changes in Nrg1 expression levels in schizophrenia still remain controversial, understanding the BACE1-cleaved Nrg1-ntf and Nrg1/ErbB4 signaling in schizophrenia neuropathogenesis is essential and important. In this review paper, we included three major parts: (1) Nrg1 structure and cleavage pattern by BACE1; (2) BACE1-dependent Nrg1 cleavage associated with schizophrenia in human studies; and (3) Animal studies of Nrg1 and BACE1 mutations with behavioral observations. Our review will provide a better understanding of Nrg1 in schizophrenia and a potential strategy for using BACE1 cleavage of Nrg1 as a unique biomarker for diagnosis, as well as a new therapeutic target, of schizophrenia.