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

DISC1 (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 DISC1 have indicated that loss of DISC1 functions are associated with pathological psychiatric conditions. Thus, DISC1 protein stability is a prerequisite to its goal in governing neural function, and modulating the protein stability of DISC1 may be a key target for understanding underlying pathology, as well promising drug discovery strategies. Nonetheless, a half-life of DISC1 protein has remained unexplored. Here, we determine for the first time the half-life of DISC1, which are regulated by ubiquitin-proteasome cascade. Overexpression of PDE4B2, a binding partner of DISC1, prolonged the half-life of DISC1, whereas NDEL1 does not alter DISC1 protein stability. Notably, the half-life of DISC1 is diminished under hypoxia stress by increasing protein degradation of DISC1, suggesting that alteration of DISC1 stability may be involved in hypoxia stress-mediated pathological conditions, such as ischemic stroke.