Single-cell transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species [human_scRNAseq]

Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease. Overall design: We selected 10 individuals from archived tissue collected by the National Prion Clinic. For our control group, we included frontal cortex samples from individuals with low-level AD pathology or pathological ageing provided by the Queen Square Brain Bank. These samples (N = 10) were matched for sex (male = 4 sCJD and 5 controls; female = 6 sCJD and 5 controls) but not age (mean age for sCJD = 70.4 years, SD = 8.6; mean age for controls = 83.7 years, SD = 8.6). We were also able to source 3 non-dominant frontal lobe biopsy samples from sCJD patients. The control samples for this group included frontal lobe biopsies from non-neurodegenerative disease controls with mixed clinical diagnoses and only non-specific minor histological changes (pathological non-diagnostic samples), provided by BRAIN UK. These samples (N = 3) were sampled similarly to the biopsies and individuals were matched for sex (male = 2 sCJD and 2 controls; female = 1 sCJD and 1 control) while the age was matched only partially (mean age for sCJD = 56.6, SD = 13.3; mean age for controls = 60.6, SD = 3.3).