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.
Molecular Psychiatry Program, Department of Psychiatry, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Sandeep Kumar
SK
Barodia
Molecular Psychiatry Program, Department of Psychiatry, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
Sang Ki
SK
Park
Molecular Psychiatry Program, Department of Psychiatry, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Koko
K
Ishizuka
Molecular Psychiatry Program, Department of Psychiatry, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: asawa1@jhmi.edu.
Akira
A
Sawa
Molecular Psychiatry Program, Department of Psychiatry, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA. Electronic address: akamiya1@jhmi.edu.
Atsushi
A
Kamiya
D000818:Animals; D015687:Cell Hypoxia; D006207:Half-Life; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016716:PC12 Cells; D059748:Proteolysis; D051381:Rats
C498795:Disc1 protein, rat; D009419:Nerve Tissue Proteins
Disrupted in schizophrenia 1 (DISC1); Hypoxia; Oxygen–glucose deprivation; Protein half-life; Ubiquitin-proteasome system