single nucleus RNA sequencing of cells from across the whole mouse brain in a mouse model of ALS

The mouse brain is a complex tissue with many cell types including distinct populations of neurons, astrocytes, and microglia. We examined cell type specific gene expression in cells across the whole brain of rNLS8 mice that express doxycycline suppressible human TDP-43 (hTDP-43) with a defective nuclear localization signal (hTDP-43?NLS) regulated by the NEFH promoter, at a timepoint when they are strongly symptomatic but preceeding robust neurodegeneration. Overall design: For this study we employed transgenic mice carrying a transgene enabling inducible neuronal expression of human TDP-43 with a deletion of its nuclear localization signal (rNLS8 mice) as a model of ALS and FTLD-TDP. The transgene was induced in adult mice, and brains were harvested after 4 weeks, when the mice were strongly symptomatic. Brains were split down the midline, and whole half-brains were used for single nucleus RNA sequencing (snRNAseq). Cell-type specific changes in gene expression were observed comparing control and rNLS8 mice.