TY - JOUR
T1 - Half-life of DISC1 protein and its pathological significance under hypoxia stress
AU - Barodia, Sandeep Kumar
AU - Park, Sang Ki
AU - Ishizuka, Koko
AU - Sawa, Akira
AU - Kamiya, Atsushi
N1 - Funding Information:
We thank Drs. Peter Espenshade and Wei Shao for sharing their lab equipments toward the successful completion of this work. We thank Dr. Miles Houslay for the kind gift of PDE4B2 expression construct and critical discussions. We thank Ms. Yukiko Lema, Mrs. Maxwell Towe, and Michael Ballinger for organizing the manuscript. This work was supported by Janssens Pharmaceuticals Inc. through a collaborative drug discovery project involving the Brain Science Institute at Johns Hopkins University School of Medicine (A.S., A.K.), MH-091230 (A.K.), AT-008547 (A.K.), MH-069853 (A.S.), MH-092443 (A.S.), MH-105660 (K.I., A.S.), and MH-094268 (A.S., A.K.).
Publisher Copyright:
© 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
KW - Disrupted in schizophrenia 1 (DISC1)
KW - Hypoxia
KW - Oxygen-glucose deprivation
KW - Protein half-life
KW - Ubiquitin-proteasome system
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U2 - 10.1016/j.neures.2015.02.008
DO - 10.1016/j.neures.2015.02.008
M3 - Article
C2 - 25738396
AN - SCOPUS:84937635587
SN - 0168-0102
VL - 97
SP - 1
EP - 6
JO - Neuroscience Research
JF - Neuroscience Research
ER -