Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease
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 fe...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54579-2 |
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| author | Jessy A. Slota Lise Lamoureux Kathy L. Frost Babu V. Sajesh Stephanie A. Booth |
| author_facet | Jessy A. Slota Lise Lamoureux Kathy L. Frost Babu V. Sajesh Stephanie A. Booth |
| author_sort | Jessy A. Slota |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cfd0ccc79b654391a0ee9b3bc2f48c8c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cfd0ccc79b654391a0ee9b3bc2f48c8c2024-11-24T12:33:11ZengNature PortfolioNature Communications2041-17232024-11-0115111910.1038/s41467-024-54579-2Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s diseaseJessy A. Slota0Lise Lamoureux1Kathy L. Frost2Babu V. Sajesh3Stephanie A. Booth4Mycobacteriology, Vector-Borne and Prion Diseases Division, National Microbiology Laboratory, Public Health Agency of CanadaMycobacteriology, Vector-Borne and Prion Diseases Division, National Microbiology Laboratory, Public Health Agency of CanadaMycobacteriology, Vector-Borne and Prion Diseases Division, National Microbiology Laboratory, Public Health Agency of CanadaMycobacteriology, Vector-Borne and Prion Diseases Division, National Microbiology Laboratory, Public Health Agency of CanadaMycobacteriology, Vector-Borne and Prion Diseases Division, National Microbiology Laboratory, Public Health Agency of CanadaAbstract 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.https://doi.org/10.1038/s41467-024-54579-2 |
| spellingShingle | Jessy A. Slota Lise Lamoureux Kathy L. Frost Babu V. Sajesh Stephanie A. Booth Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease Nature Communications |
| title | Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease |
| title_full | Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease |
| title_fullStr | Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease |
| title_full_unstemmed | Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease |
| title_short | Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease |
| title_sort | single cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with alzheimer s disease |
| url | https://doi.org/10.1038/s41467-024-54579-2 |
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