title: Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects.
abstract: Transcription factors play important roles in the control of neuronal function in physiological and pathological conditions. We previously reported reduced levels of transcription factor SP4 protein, but not transcript, in the cerebellum in bipolar disorder and associated with more severe negative symptoms in schizophrenia. We have recently reported phosphorylation of Sp4 at S770, which is regulated by membrane depolarization and NMDA receptor activity. The aim of this study was to investigate SP4 S770 phosphorylation in bipolar disorder and its association with negative symptoms in schizophrenia, and to explore the potential relationship between phosphorylation and protein abundance. Here we report a significant increase in SP4 phosphorylation in the cerebellum, but not the prefrontal cortex, of bipolar disorder subjects (n=10) (80% suicide) compared to matched controls (n=10). We found that SP4 phosphorylation inversely correlated with SP4 levels independently of disease status in both areas of the human brain. Moreover, SP4 phosphorylation in the cerebellum positively correlated with negative symptoms in schizophrenia subjects (n=15). Further, we observed that a phospho-mimetic mutation in truncated Sp4 was sufficient to significantly decrease Sp4 steady-state levels, while a non-phosphorylatable mutant showed increased stability in cultured rat cerebellar granule neurons. Our results indicate that SP4 S770 phosphorylation is increased in the cerebellum in bipolar disorder subjects that committed suicide and in severe schizophrenia subjects, and may be part of a degradation signal that controls Sp4 abundance in cerebellar granule neurons. This opens the possibility that modulation of SP4 phosphorylation may contribute to the molecular pathophysiology of psychotic disorders.
authors.affiliation: Unitat de recerca, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Dr. Antoni Pujadas, 42, 08830- Sant Boi de Llobregat, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pinacho
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.|Cell, Molecular and Developmental Biology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.
authors.forename: Gregory
authors.initials: G
authors.lastname: Saia
authors.affiliation: Departamento de Farmacología, Universidad del País Vasco / Euskal Herriko Unibertsitatea UPV/EHU, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, B Sarriena s/n 48940-Leioa, Bizkaia, Spain.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.
authors.forename: Grace
authors.initials: G
authors.lastname: Gill
authors.affiliation: Unitat de recerca, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Dr. Antoni Pujadas, 42, 08830- Sant Boi de Llobregat, Barcelona, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Ramos
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism; D055550:Protein Stability; D051381:Rats; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D051706:Sp4 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C497124:SP4 protein, human; D051706:Sp4 Transcription Factor
keywords: Bipolar disorder; Cerebellum; Phosphorylation; Protein stability; Schizophrenia; Sp4 transcription factor