5ba69378b3fe1035d6c795bb31575a8f pmc_34576238.pdf ff1316c3f1c223543a1a97e764a3da5c4f843110 pmc_34576238.pdf d171f3d488058e597a9ec756e656ef5e9f809dad45fb4c8f2a9fa7ceef3d182f pmc_34576238.pdf Title: Analysis of Molecular Networks in the Cerebellum in Chronic Schizophrenia: Modulation by Early Postnatal Life Stressors in Murine Models Subject: Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography–tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context. Keywords: proteomics; postmortem brain; pathways; networks; schizophrenia Author: América Vera-Montecinos, Ricard Rodríguez-Mias, Karina S. MacDowell, Borja García-Bueno, Álvaro G. Bris, Javier R. Caso, Judit Villén and Belén Ramos Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Sep 17 16:37:13 2021 CEST ModDate: Fri Sep 17 16:53:24 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 14489495 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NMGAFZ+URWPalladioL-Ital Type 1 Custom yes yes no 10 0 LUBSBT+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 ARKGPG+URWPalladioL-Roma Type 1 Custom yes yes no 19 0 ULTSPI+VnURWPalladioL-Bold Type 1 Custom yes yes no 23 0 HMTVAK+VnURWPalladioL Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 36 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 DIPFXD+CMSY10 Type 1 Builtin yes yes no 98 0 JCMBAC+URWPalladioL-BoldItal Type 1 Custom yes yes no 108 0 CAMXTK+EURM10 Type 1 Builtin yes yes no 164 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:56:48 CEST RepresentationInformation: pmc_34576238.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:05:47 CEST Size: 14489495 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 480 FreeObjects: 9 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Quantitative Proteomic Analyses in Cerebellum in Chronic Schizophrenia Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Gene Ontology Enrichment Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Network Generation from Enriched Pathways in the Cerebellum Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Analysis of Altered Robust Candidates in Double-Hit Stress Murine Models Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Up-Regulated Proteins Related to Stress and Axonal Functions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Vesicle-Mediated Transport Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Axon Guidance Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Down-Regulated Proteins Related to Mitochondrial Disease, Energy Functions and Immune Response Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: Energy Metabolism Module Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Neutrophil Degranulation Module Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Methods and Materials Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Children: Item: Title: Postmortem Human Brain Tissue Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Label Free Quantification Proteomic Analysis Mass Spectrometry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Bioinformatic Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Stress Murine Models Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Info: Title: Analysis of Molecular Networks in the Cerebellum in Chronic Schizophrenia: Modulation by Early Postnatal Life Stressors in Murine Models Author: América Vera-Montecinos, Ricard Rodríguez-Mias, Karina S. MacDowell, Borja García-Bueno, Álvaro G. Bris, Javier R. Caso, Judit Villén and Belén Ramos Subject: Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context. 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653, 142, 663 Annotation: Subtype: Link Rect: 86, 617, 175, 628 Annotation: Subtype: Link Rect: 291, 617, 328, 628 Annotation: Subtype: Link Rect: 265, 594, 494, 605 Annotation: Subtype: Link Rect: 127, 583, 165, 594 Annotation: Subtype: Link Rect: 171, 583, 207, 594 Annotation: Subtype: Link Rect: 350, 548, 388, 559 Annotation: Subtype: Link Rect: 519, 502, 557, 513 Annotation: Subtype: Link Rect: 59, 492, 95, 502 Annotation: Subtype: Link Rect: 308, 468, 345, 479 Checksum: e35d65ad Type: CRC32 Checksum: 5ba69378b3fe1035d6c795bb31575a8f Type: MD5 Checksum: ff1316c3f1c223543a1a97e764a3da5c4f843110 Type: SHA-1