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| Home > Publications Database > Regulation of gene expression in specific mouse brain cells during neurodegenerative prion diseases |
| Home > Publications Database > Regulation of gene expression in specific mouse brain cells during neurodegenerative prion diseases |
| Dissertation / PhD Thesis | DZNE-2020-00221 |
2018
Bonn
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Please use a persistent id in citations: urn:nbn:de:hbz:5n-50630
Abstract: Why neurodegenerative diseases target specific brain regions is poorly understood. We hypothesize that this selective vulnerability is caused by specific brain cells in these regions having unique strategies and capacities to cope with various disease related protein conformers that ultimately fail.To study how specific cell types in the mouse brain respond to a neurodegenerative disease we used prion infection (RML scrapie strain) as a model of neurodegenerative disease. RML infection was combined with the RiboTag method to isolate ribosome associated mRNA from specific brain cell types. Mice expressing the epitope-tagged ribosomes specifically in astrocytes or subsets of neurons, including glutamatergic, GABAergic, parvalbumin or somatostatin neurons, were injected with brain homogenate from either normal or prion infected mice. Changes to gene expression were analyzed by next generation sequencing at a stage when clinical signs first become apparent (18 wpi) and at a much earlier stage (10 wpi) in the disease process. Neuropathological changes like microglia activation, astrogliosis, aggregated prions and spongiosis were analyzed by different IHC stainings. This work gives clues into which cells are affected earliest and how they respond to the emerging disease. lnvestigating cell-type-specific mechanisms of selective vulnerability are needed for a better understanding of mechanism in NOs and developing therapies.At disease onset (18 wpi) an extensive regulation of gene expression is detectable, although mice show obviously no changes in their phenotype. Gene expression changes at 18 wpi were drastic with too many changes for an in-depth gene expression analysis of which cells were most affected and what were the most changed molecular pathways. To detect which cells are affected earliest and how they respond to the emerging disease the early disease time point (10 wpi) was chosen for analysis. First, we found glutamatergic neurons were changing. However, PV neurons and SST neurons were unaltered. Moreover, we found that astrocytes are highly altered and probably the most and earliest affected cell type. GABAergic neurons were found to be changed depending on the statistical output of two different next generation sequencing data analyses.Glutamatergic neurons have more up regulation within differentially expressed genes, whereas GABAergic neurons and astrocytes show more down regulation within the differentially expressed genes. Comparison of the differentially expressed genes of the different cell types with little overlap demonstrates that individual cell types respond to the same RML induced neurodegeneration differently.Canonical pathway analysis show actively translated mRNAs changed in the astrocytes are mainly ribosomal proteins and members of the electron transport chain leading to an impairment or change of gene expression and a mitochondrial dysfunction. Glutametergic gene ontology analysis possess genes associated to actin, actin binding, cytoskeleton, cellular transport and signaling, probably leading to a stabilization of the cell and maintenance of essential glutamatergic neuron functions like signal transduction. GABAergic neurons show changes based on gene read analysis in genes involved in circadian rhythm signaling. All these circadian rhythm genes are also known to be involved in oxidative stress response.
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