title: Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies.
abstract: Public transcriptomic studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal disorders. Here, we apply a transcriptome-wide analysis to discover genes with gender-specific expression and significant alterations in public postmortem brain tissue from Alzheimer's disease (AD) patients compared to controls. We identify the sex-linked ubiquitin-specific peptidase 9 (USP9) as an outstanding candidate gene with highly significant expression differences between the genders and male-specific underexpression in AD. Since previous studies have shown that USP9 can modulate the phosphorylation of the AD-associated protein MAPT, we investigate functional associations between USP9 and MAPT in further detail. After observing a high positive correlation between the expression of USP9 and MAPT in the public transcriptomics data, we show that USP9 knockdown results in significantly decreased MAPT expression in a DU145 cell culture model and a concentration-dependent decrease for the MAPT orthologs mapta and maptb in a zebrafish model. From the analysis of microarray and qRT-PCR experiments for the knockdown in DU145 cells and prior knowledge from the literature, we derive a data-congruent model for a USP9-dependent regulatory mechanism modulating MAPT expression via BACH1 and SMAD4. Overall, the analyses suggest USP9 may contribute to molecular gender differences observed in tauopathies and provide a new target for intervention strategies to modulate MAPT expression.
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Sandra
authors.initials: S
authors.lastname: Köglsberger
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Cordero-Maldonado
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Paul
authors.initials: P
authors.lastname: Antony
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Julia Ilona
authors.initials: JI
authors.lastname: Forster
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Pierre
authors.initials: P
authors.lastname: Garcia
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Manuel
authors.initials: M
authors.lastname: Buttini
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg.
authors.forename: Alexander
authors.initials: A
authors.lastname: Crawford
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7 avenue des Hauts Fourneaux, 4362, Esch-sur-Alzette, Luxembourg. enrico.glaab@uni.lu.
authors.forename: Enrico
authors.identifier: http://orcid.org/0000-0003-3977-7469
authors.initials: E
authors.lastname: Glaab
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D024801:Tauopathies / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D015027:Zebrafish; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D064570:Ubiquitin-Specific Proteases
keywords: Alzheimer’s disease; Gender differences; Tau; Tauopathies; Transcriptomics; Zebrafish