Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease

Jessy A. Slota, Lise Lamoureux, Kathy L. Frost, Babu V. Sajesh and Stephanie A. Booth ()
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Jessy A. Slota: Public Health Agency of Canada
Lise Lamoureux: Public Health Agency of Canada
Kathy L. Frost: Public Health Agency of Canada
Babu V. Sajesh: Public Health Agency of Canada
Stephanie A. Booth: Public Health Agency of Canada

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Understanding why certain neurons are more sensitive to dysfunction and death caused by misfolded proteins could provide therapeutically relevant insights into neurodegenerative disorders. Here, we harnessed single-cell transcriptomics to examine live neurons isolated from prion-infected female mice, aiming to identify and characterize prion-vulnerable neuronal subsets. Our analysis revealed distinct transcriptional responses across neuronal subsets, with a consistent pathway-level depletion of synaptic gene expression in damage-vulnerable neurons. By scoring neuronal damage based on the magnitude of depleted synaptic gene expression, we identified a diverse spectrum of prion-vulnerable glutamatergic, GABAergic, and medium spiny neurons. Comparison between prion-vulnerable and resistant neurons highlighted baseline gene expression differences that could influence neuronal vulnerability. For instance, the neuroprotective cold-shock protein Rbm3 exhibited higher baseline gene expression in prion-resistant neurons and was robustly upregulated across diverse neuronal classes upon prion infection. We also identified vulnerability-correlated transcripts that overlapped between prion and Alzheimer’s disease. Our findings not only demonstrate the potential of single-cell transcriptomics to identify damage-vulnerable neurons, but also provide molecular insights into neuronal vulnerability and highlight commonalties across neurodegenerative disorders.

Date: 2024
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DOI: 10.1038/s41467-024-54579-2

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