Whole genome expression analysis in a mouse model of tauopathy identifies MECP2 as a possible regulator of tau pathology

Nicole M. Maphis, Shanya Jiang, Jessica Binder, Carrie Wright, Banu Gopalan, Bruce Lamb, Kiran Bhaskar

Research output: Contribution to journalArticle

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Abstract

Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer’s disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human MAPT gene under the control of endogenous human MAPT promoter and also were complete knockout for endogenous mouse tau [referred to as ‘hTauMaptKO(Duke)′ mice]. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTauMaptKO(Duke) mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha (Prkca), MECP2 (Mecp2), STRN4 (Strn4), SLC40a1 (Slc40a1), POLD2 (Pold2), PCSK2 (Pcsk2), and down-regulated genes: KRT12 (Krt12), LASS1 (Cers1), PLAT (Plat), and NRXN1 (Nrxn1). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTauMaptKO(Duke) mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTauMaptKO(Duke) mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a significant decrease in total and phosphorylated tau. Together, these results suggest that MECP2 is a potential novel regulator of tau pathology relevant to AD and tauopathies.

Original languageEnglish (US)
Article number69
JournalFrontiers in Molecular Neuroscience
Volume10
DOIs
StatePublished - Mar 17 2017

Fingerprint

Methyl-CpG-Binding Protein 2
Tauopathies
Genome
Pathology
Alzheimer Disease
Genes
Biological Phenomena
Microtubule-Associated Proteins
Cellular Structures
Knockout Mice
Small Interfering RNA
Chromatin
Disease Progression
Autopsy
Signal Transduction
Hippocampus
Cell Death
Animal Models
Phosphorylation
Gene Expression

Keywords

  • Alzheimer’s disease
  • MECP2
  • Methyl-CpG-binding protein-2
  • Microarray
  • Tau protein
  • Tau transgenic mice
  • Tauopathies

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Whole genome expression analysis in a mouse model of tauopathy identifies MECP2 as a possible regulator of tau pathology. / Maphis, Nicole M.; Jiang, Shanya; Binder, Jessica; Wright, Carrie; Gopalan, Banu; Lamb, Bruce; Bhaskar, Kiran.

In: Frontiers in Molecular Neuroscience, Vol. 10, 69, 17.03.2017.

Research output: Contribution to journalArticle

Maphis, Nicole M. ; Jiang, Shanya ; Binder, Jessica ; Wright, Carrie ; Gopalan, Banu ; Lamb, Bruce ; Bhaskar, Kiran. / Whole genome expression analysis in a mouse model of tauopathy identifies MECP2 as a possible regulator of tau pathology. In: Frontiers in Molecular Neuroscience. 2017 ; Vol. 10.
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