Regulation of gene expression in specific mouse brain cells during neurodegenerative prion disease

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.<br /> 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. Prion infection was combined with the RiboTag method to isolate ribosome associated, actively translated mRNA from specific brain cell types. Mice expressing the epitope-tagged ribosomes specifically in astrocytes or subsets of neurons, including glutamatergic, GABAergic, parvalbumin and somatostatin neurons, were injected with brain homogenate from either normal or prion infected mice. Early changes to gene expression were analyzed by next generation sequencing at a stage when clinical signs first become apparent (disease onset) and at a much earlier stage (preclinical time point) in the disease process. Neuropathological changes like microglia activation, astrogliosis, aggregated prions and spongiosis were analyzed by different immunohistochemistry stainings.<br /> This work gives clues into which cells are affected earliest and how they respond to the emerging disease. Investigating cell-type-specific mechanisms of selective vulnerability are needed for a better understanding of mechanism in neurodegenerative diseases and developing therapies.