{"database":"biostudies-arrayexpress","file_versions":[],"scores":null,"additional":{"submitter":["Rodrigo Senovilla-Ganzo"],"organism":["Mus musculus"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/E-MTAB-16400"],"description":["Alzheimer’s disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-β (Aβ), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that Aβ exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, Aβ impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Gö6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between Aβ/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD."],"repository":["biostudies-arrayexpress"],"sample_protocol":["Library Construction - Libraries were prepared with the NEBNext Single Cell/Low Input RNA Library Prep Kit for Illumina (#E6420S, New England Biolabs) and NEBNext Multiplex Oligos for Illumina (Index Primers 1 12) (#E7335S, New England Biolabs), following the corresponding instruction manual (Version5.0_5/20). The protocol started with 10 ng total RNA when available (otherwise, entire sample). Full-length cDNA was generated by template switching, followed by cDNA amplification and cleanup; 1 μl amplified cDNA was evaluated on an Agilent High Sensitivity DNA chip (#5067-4626, Agilent Technologies).","Nucleic Acid Extraction - RNA was isolated from oligodendrocytes using the RNA Micro Kit (Qiagen).","Sequencing - Fragmentation, end repair, tailing, Illumina adapter ligation, and barcoding PCR were performed per kit instructions, with amplification cycles adjusted to input cDNA amount. Libraries were visualized on the Agilent 2100 Bioanalyzer and quantified with the Qubit dsDNA HS DNA Kit (#Q32854, Thermo Fisher Scientific). Base calls (BCL) were converted into FASTQ files utilizing Illumina Inc.’s package bcl2fastq, and quality control was performed with FastQC (Andrews, 2020).","Sample Collection - Samples derive from MACS-isolated O4+ oligodendrocytes."],"figure_sub":["Organization","MINSEQE Score","Assays and Data","Processed Data","MAGE-TAB Files"],"data_protocol":["Data Transformation - HTSeq was used to obtain count matrix from BAM alignments. DESeq2 was then employed to normalize sequencing depth and regress batch factors. In published plots, rlog count matrix was employed.","Sequence Alignment - Reads were aligned with STAR v2.7.1 (Dobin et al., 2013) against the Ensembl genome of Mus musculus (GRCm39.dna.primary_assembly.fa and GRCm39.104.gtf), and expression counts were obtained using htseq-count (-s no) (Anders et al., 2015)."],"omics_type":["Metabolomics","Unknown","Transcriptomics","Genomics","Proteomics"],"instrument_platform":["Single Cell/Low Input RNA Library Prep Kit for Illumina (#E6420S, New England Biolabs)","STAR","MACS","Illumina HiScanSQ","RNA Micro Kit (Qiagen)."],"study_type":["RNA-seq of coding RNA"],"species":["Mus musculus"],"pubmed_title":["PKC-dependent MYRF dysregulation links Aβ pathology to oligodendrocyte, myelin and cognitive alterations in Alzheimer’s disease"],"pubmed_authors":["Uxue Balantzategi1, 2 , Adhara Gaminde-Blasco1, 2 , Neus Alcañiz1, 2 , Juanma Ramirez3 , Rodrigo Senovilla-Ganzo1, 2 , Nagore Hernández-Pinedo4, 5 , Mario Fernandez-Ballester2, Federico N. Soria2, 6 , Alerie G. de la Fuente7 , Fernando García-Moreno1, 2, 6 , Estibaliz Capetillo-Zarate1, 2, 6 , Ugo Mayor3, 6 , Edgar Soria-Gómez1, 2, 6 , José L. Zugaza2, 6, 8 , Elena Alberdi1,","Rodrigo Senovilla-Ganzo"],"additional_accession":[]},"is_claimable":false,"name":"PKC-dependent MYRF dysregulation links Aβ pathology to oligodendrocyte, myelin and cognitive alterations in Alzheimer’s disease","description":"Alzheimer’s disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-β (Aβ), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that Aβ exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, Aβ impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Gö6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between Aβ/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD.","dates":{"release":"2025-12-31T00:00:00Z","modification":"2026-05-28T15:08:21.431Z","creation":"2025-12-17T22:54:51.071Z"},"accession":"E-MTAB-16400","cross_references":{"ENA":["ERP186722"],"EFO":["EFO_0002944","EFO_0004170","EFO_0004917","EFO_0005518","EFO_0003816","EFO_0003738","EFO_0004184"]}}