Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for TauopathiesReport as inadecuate




Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies - Download this document for free, or read online. Document in PDF available to download.

Molecular Neurobiology

pp 1–15

First Online: 23 November 2016Received: 22 May 2016Accepted: 14 November 2016

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.

KeywordsTranscriptomics Tau Tauopathies Alzheimer’s disease Gender differences Zebrafish Sandra Köglsberger, Maria Lorena Cordero-Maldonado and Paul Antony contributed equally to this study.

Electronic supplementary materialThe online version of this article doi:10.1007-s12035-016-0299-z contains supplementary material, which is available to authorized users.

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Author: Sandra Köglsberger - Maria Lorena Cordero-Maldonado - Paul Antony - Julia Ilona Forster - Pierre Garcia - Manuel Buttini

Source: https://link.springer.com/







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