Half-life of DISC1 protein and its pathological significance under hypoxia stress

Abstract

DISCI (disrupted in schizophrenia 1) is an intracellular scaffolding molecule which regulates multiple signaling pathways for neural cell differentiation and function. Many biological studies utilizing animal models of DISCI have indicated that loss of DISCI functions are associated with pathological psychiatric conditions. Thus, DISCI protein stability is a prerequisite to its goal in governing neural function, and modulating the protein stability of DISCI may be a key target for understanding underlying pathology, as well promising drug discovery strategies. Nonetheless, a half-life of DISCI protein has remained unexplored. Here, we determine for the first time the half-life of DISCI, which are regulated by ubiquitin-proteasome cascade. Overexpression of PDE4B2, a binding partner of DISCI, prolonged the half-life of DISCI, whereas NDEL1 does not alter DISCI protein stability. Notably, the half-life of DISCI is diminished under hypoxia stress by increasing protein degradation of DISCI, suggesting that alteration of DISCI stability may be involved in hypoxia stress-mediated pathological conditions, such as ischemic stroke. (C) 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.