The cell type resolved mouse transcriptome in neuron-enriched brain tissues from the hippocampus and cerebellum during prion disease. Majer A*, Medina SJ*, Sorensen D*, Martin MJ*, Frost KL*, Phillipson C*, Manguiat K*, Booth SA*. Sci Rep 2019 Jan 31; 9(1):1099. doi: https://doi.org/10.1038/s41598-018-37715-z
This science story describes NML research on prion disease, a group of neurodegenerative diseases that cause rapid cognitive decline. The use of bioinformatics to identify genes involved in these diseases can help in the detection and diagnosis of these neurological diseases that impact the health of Canadians.
What was known about this area prior to your work, and why was the research done?
Prions are misfolded proteins that replicate in the brain eventually resulting in the death of cells. The brain tissue takes on a spongy appearance and patients display symptoms of neurodegenerative disease that rapidly and invariably leads to death. No drugs are available to halt this process. Although our understanding of how prions replicate and spread has progressed rapidly in recent years, the mechanism by which cell death occurs is poorly understood. The brain contains multiple cell types and complex connection networks making it difficult to resolve the toxic pathways that are triggered by prions in infected cells. In this study we used microdissection, a method to precisely excise small numbers of infected neuronal cells from brain tissue, to resolve specific cell type RNA molecules and gene expression, referred to as the transcriptome, throughout disease progression.
What are your most significant findings from this work?
Determining changes in the transcriptome of small numbers of cells is technically challenging. These transcriptome changes show how cells react to biological conditions, in this case prion disease. This, and our previous study (referenced below) are the first studies to apply cell-type resolved transcriptome analysis in prion diseases. By studying brains of diseased mice and using advanced bioinformatics analysis, we determined gene expression responses in dying cells. This genetic activity provides clues to disease progression and potential pre-clinical markers linked to cell death. We analysed different populations of cells from mice infected with two prion strains, and identified a number of genes not previously associated with neurodegeneration. The identified genes help determine biological processes specific to the studied cell types and may improve our understanding of prion replication and disease.
What are the implications or impact of the research?
One of the biggest outstanding questions in prion research is: “how do neurons die?” Only recently have researchers had the tools to investigate what triggers neuronal death. The genes we identified provide important clues for the targeted development of therapeutics to address this public health issue impacting many Canadians. The genes can also be used to help determine the stage of the disease and to monitor the effectiveness of treatment. Further, these genes may also be common to neurodegenerative diseases such as Alzheimer’s disease, the most frequent cause of dementia in Canada.
Additional References of Significance:
- Majer A*, Medina SJ*, Niu Y*, Abrenica B*, Manguiat KJ*, Frost KL*, Philipson CS*, Sorensen DL*, Booth SA*. Early mechanisms of pathobiology are revealed by transcriptional temporal dynamics in hippocampal CA1 neurons of prion infected mice. PLoS Pathog 2012; 8(11):e1003002. doi: https://doi.org/10.1371/journal.ppat.1003002