Leslie G Nucifora1, Matthew L MacDonald1, Brian J Lee1, Matthew E Peters1, Alexis L Norris1, Benjamin C Orsburn1, Kun Yang1, Kelly Gleason1, Russell L Margolis1, Jonathan Pevsner1, Carol A Tamminga1, Robert A Sweet1, Christopher A Ross1, Akira Sawa1, Frederick C Nucifora1. 1. The Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore (L.G. Nucifora, Lee, Peters, Yang, Margolis, Pevsner, Ross, Sawa, F.C. Nucifora); the Departments of Psychiatry and Neurology, University of Pittsburgh, and the VISN 4 Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh (MacDonald, Sweet); the Department of Neurology, Kennedy Krieger Institute, Baltimore (Norris, Pevsner); the Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore (Norris, Pevsner, Ross, Sawa); Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Md. (Orsburn); the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas (Gleason, Tamminga); the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore (Margolis, Ross, Sawa, F.C. Nucifora); Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore (Lee, Sawa); the Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore (Ross).
Abstract
OBJECTIVE: The mechanisms leading to schizophrenia are likely to be diverse. However, there may be common pathophysiological pathways for subtypes of the disease. The authors tested the hypothesis that increased protein insolubility and ubiquitination underlie the pathophysiology for a subtype of schizophrenia. METHODS: Prefrontal cortex and superior temporal gyrus from postmortem brains of individuals with and without schizophrenia were subjected to cold sarkosyl fractionation, separating proteins into soluble and insoluble fractions. Protein insolubility and ubiquitin levels were quantified for each insoluble fraction, with normalization to total homogenate protein. Mass spectrometry analysis was then performed to identify the protein contents of the insoluble fractions. The potential biological relevance of the detected proteins was assessed using Gene Ontology enrichment analysis and Ingenuity Pathway Analysis. RESULTS: A subset of the schizophrenia brains showed an increase in protein insolubility and ubiquitination in the insoluble fraction. Mass spectrometry of the insoluble fraction revealed that brains with increased insolubility and ubiquitination exhibited a similar peptide expression by principal component analysis. The proteins that were significantly altered in the insoluble fraction were enriched for pathways relating to axon target recognition as well as nervous system development and function. CONCLUSIONS: This study suggests a pathological process related to protein insolubility for a subset of patients with schizophrenia. Determining the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways underlying the clinical phenotype in some patients with major mental illness as well as to improved nosology and identification of novel therapeutic targets.
OBJECTIVE: The mechanisms leading to schizophrenia are likely to be diverse. However, there may be common pathophysiological pathways for subtypes of the disease. The authors tested the hypothesis that increased protein insolubility and ubiquitination underlie the pathophysiology for a subtype of schizophrenia. METHODS: Prefrontal cortex and superior temporal gyrus from postmortem brains of individuals with and without schizophrenia were subjected to cold sarkosyl fractionation, separating proteins into soluble and insoluble fractions. Protein insolubility and ubiquitin levels were quantified for each insoluble fraction, with normalization to total homogenate protein. Mass spectrometry analysis was then performed to identify the protein contents of the insoluble fractions. The potential biological relevance of the detected proteins was assessed using Gene Ontology enrichment analysis and Ingenuity Pathway Analysis. RESULTS: A subset of the schizophrenia brains showed an increase in protein insolubility and ubiquitination in the insoluble fraction. Mass spectrometry of the insoluble fraction revealed that brains with increased insolubility and ubiquitination exhibited a similar peptide expression by principal component analysis. The proteins that were significantly altered in the insoluble fraction were enriched for pathways relating to axon target recognition as well as nervous system development and function. CONCLUSIONS: This study suggests a pathological process related to protein insolubility for a subset of patients with schizophrenia. Determining the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways underlying the clinical phenotype in some patients with major mental illness as well as to improved nosology and identification of novel therapeutic targets.
Entities:
Keywords:
Aggregation; Protein Insolubility; Protein Misfolding; Schizophrenia; Subtype; Ubiquitination
Authors: Juan R Bustillo; Joel Upston; Elizabeth Grace Mayer; Thomas Jones; Andrew A Maudsley; Charles Gasparovic; Mauricio Tohen; Rhoshel Lenroot Journal: Neuropsychopharmacology Date: 2020-05-13 Impact factor: 7.853
Authors: Evangelos Vassos; Jiaqi Kou; Sarah Tosato; Jessye Maxwell; Charlotte A Dennison; Sophie E Legge; James T R Walters; Michael J Owen; Michael C O'Donovan; Gerome Breen; Cathryn M Lewis; Patrick F Sullivan; Christina Hultman; Mirella Ruggeri; Muriel Walshe; Elvira Bramon; Sarah E Bergen; Robin M Murray Journal: Schizophr Bull Date: 2022-01-21 Impact factor: 9.306