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1.
Nat Med ; 25(1): 152-164, 2019 01.
Article in English | MEDLINE | ID: mdl-30510257

ABSTRACT

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.


Subject(s)
Dementia/genetics , Evolution, Molecular , Gene Regulatory Networks , Neurodegenerative Diseases/genetics , Animals , Cell Death/genetics , Disease Models, Animal , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Gene Expression Regulation , Genetic Predisposition to Disease , Genetic Vectors/metabolism , Humans , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/genetics , MicroRNAs/metabolism , Proteomics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , Transcriptome/genetics , tau Proteins/metabolism
2.
Neuropharmacology ; 148: 11-20, 2019 04.
Article in English | MEDLINE | ID: mdl-30594698

ABSTRACT

24S-hydroxycholesterol (24HC) is the major metabolic breakdown product of cholesterol in the brain. Among its other effects on neurons, 24HC modulates N-methyl-d-aspartate (NMDA or GluN) receptors, but our understanding of this mechanism is poor. We used whole-cell patch clamp recordings and various pharmacological approaches in mouse brain slices to record isolated NMDAR-mediated (INMDA) tonic and evoked synaptic currents. 24HC (1 µΜ) significantly enhanced tonic, but not evoked, INMDA of dentate gyrus granule cells. The INMDA had both GluN2A and GluN2B-mediated components. Preincubation of the slices with PEAQX (a GluN2A antagonist) or Ro25-6981 (a GluN2B antagonist) dramatically changed the INMDA modulatory potential of 24HC. Ro25-6981 blocked the enhancing effect of 24HC on tonic INMDA, while preincubation with PEAQX had no effect. In cholesterol 24-hydroxylase (CYP46A1) knockout mice, in sharp contrast to WT, 24HC slightly decreased the tonic INMDA of granule cells. Furthermore, 24HC had no effect on tonic INMDA of dentate gyrus parvalbumin interneurons (PV-INs), known to express different GluN subunits than granule cells. Taken together, our results revealed a specific enhancement of GluN2B-containing NMDARs by 24HC, indicating a novel endogenous pathway to influence a subclass of NMDARs critically involved in cortical plasticity and in numerous neurological and psychiatric disorders.


Subject(s)
Dentate Gyrus/physiology , Hydroxycholesterols/metabolism , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Cholesterol 24-Hydroxylase/genetics , Dentate Gyrus/drug effects , Evoked Potentials/physiology , Excitatory Postsynaptic Potentials/physiology , Interneurons/physiology , Male , Mice , Mice, Knockout , Neurons/drug effects , Neurons/physiology , Phenols/pharmacology , Piperidines/pharmacology , Quinoxalines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Synaptic Potentials/physiology
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