Jesús Muñoz-Estrada1, Gloria Benítez-King, Carlos Berlanga, Isaura Meza. 1. Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico, Mexico; Laboratory of Neuropharmacology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico, Mexico.
Abstract
BACKGROUND: DISC1 (Disrupted-In-Schizophrenia-1) is considered a genetic risk factor for schizophrenia (SZ) and bipolar disorder (BD). DISC1 regulates microtubule stability, migration, and cAMP signaling in mammalian cell lines and mouse brain tissue. cAMP is a regulator of microtubule organization and migration in neurons. Aberrant microtubule organization has been observed in olfactory neuronal precursors (ONP) derived from patients with SZ and BD, which suggests involvement of DISC1 and cAMP. However, the biology of DISC1 in the physiopathology of psychiatric conditions remains elusive. AIMS: Herein, utilizing ONP obtained from SZ, BD patients and healthy subjects, we have studied DISC1 expression, protein levels, and subcellular distribution by qRT-PCR, immunoblotting, subcellular fractionation, and confocal microscopy. Cell migration and cAMP accumulation were assessed by Transwell and PKA competition assays. RESULTS: We found increased levels of the 75-kDa DISC1 isoform in total cell extracts of ONP from patients with SZ and BD compared with controls. Subcellular distribution showed a significant decrease of cytoplasmic DISC1 concomitant with its augmented levels in transcription sites. Moreover, significant cAMP accumulation and diminished migration were also observed in patients' cells. CONCLUSION: Alterations of DISC1 levels and its cellular distribution, which negatively modify cAMP homeostasis, microtubule organization, and cell migration, in ONP from patients with SZ and BD, suggest that their presence in early stages of brain development may impact brain maturation and function.
BACKGROUND:DISC1 (Disrupted-In-Schizophrenia-1) is considered a genetic risk factor for schizophrenia (SZ) and bipolar disorder (BD). DISC1 regulates microtubule stability, migration, and cAMP signaling in mammalian cell lines and mouse brain tissue. cAMP is a regulator of microtubule organization and migration in neurons. Aberrant microtubule organization has been observed in olfactory neuronal precursors (ONP) derived from patients with SZ and BD, which suggests involvement of DISC1 and cAMP. However, the biology of DISC1 in the physiopathology of psychiatric conditions remains elusive. AIMS: Herein, utilizing ONP obtained from SZ, BD patients and healthy subjects, we have studied DISC1 expression, protein levels, and subcellular distribution by qRT-PCR, immunoblotting, subcellular fractionation, and confocal microscopy. Cell migration and cAMP accumulation were assessed by Transwell and PKA competition assays. RESULTS: We found increased levels of the 75-kDa DISC1 isoform in total cell extracts of ONP from patients with SZ and BD compared with controls. Subcellular distribution showed a significant decrease of cytoplasmic DISC1 concomitant with its augmented levels in transcription sites. Moreover, significant cAMP accumulation and diminished migration were also observed in patients' cells. CONCLUSION: Alterations of DISC1 levels and its cellular distribution, which negatively modify cAMP homeostasis, microtubule organization, and cell migration, in ONP from patients with SZ and BD, suggest that their presence in early stages of brain development may impact brain maturation and function.
Authors: B Ian Hutchins; L Damla Kotan; Carol Taylor-Burds; Yusuf Ozkan; Paul J Cheng; Fatih Gurbuz; Jean D R Tiong; Eda Mengen; Bilgin Yuksel; A Kemal Topaloglu; Susan Wray Journal: Endocrinology Date: 2016-03-25 Impact factor: 4.736