Nucleocytoplasmic Shuttling of Dysbindin-1, a Schizophrenia-related Protein, Regulates Synapsin I Expression

Cuiqing Zhu,Guanghui Wang,Yuxia Xu,Erkang Fei,Xiaochuan Ma,Jie Yan,Jiangning Zhou,Ting Xue

doi:10.1074/jbc.m110.107912

Abstract

Dysbindin-1 is a 50-kDa coiled-coil-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. Here, we show that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1-mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia.

Highlights

Dysbindin-1 is widely and abundantly expressed in rodent and human brains and has important functions in the cytoplasm [1, 20, 32]
To examine if dysbindin-1 could be localized to the nucleus, we generated an EGFP-tagged dysbindin-1A construct and transfected it into human embryonic kidney 293 (HEK293) cells, N2a cells, and primary cultured neuronal cells from rat hippocampal formation (HF), respectively
Using fractionation analysis combined with immunoblot analysis, we observed that endogenous dysbindin-1A was decreased in the cytoplasmic fraction and increased in the nuclear fraction in N2a cells treated with leptomycin B (LMB) (Fig. 4D)

Summary

Introduction

Dysbindin-1 is widely and abundantly expressed in rodent and human brains and has important functions in the cytoplasm [1, 20, 32]. It was reported that dysbindin-1 regulates the expression of synapsin I in rat primary cortical neuronal cultures [6]. Our data suggest that dysbindin transcriptionally regulates synapsin I gene expression dependent on its nuclear localization.

Results

Conclusion