RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection

Prion diseases and prion-like disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins. Ablating microglia in prion-infected brain by treatment with the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, PLX5622, increased accumulation of misfolded prion protein and decreased survival time.

To better understand the role of glia during neurodegeneration, researchers from the National Institute of Allergy and Infectious Diseases used RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice. Comparisons were also made between PLX5622-treated prion-infected mice and untreated prion-infected mice to assess mechanisms involved in disease acceleration in the absence of microglia.

RNA-seq and network analysis suggested that microglia responded to prion infection through activation of integrin CD11c/18 and did not adopt the expression signature associated with other neurodegenerative disease models. Instead, microglia acquired an alternative molecular signature late in the disease process. Furthermore, astrocytes expressed a signature pattern of genes which appeared to be specific for prion diseases. Comparisons were also made with prion-infected mice treated with PLX5622 to assess the impact of microglia ablation on astrocyte gene expression during prion infection. In the presence of microglia, a unique mix of transcripts associated with A1- and A2-reactive astrocytes was increased in brains of prion-infected mice. After ablation of microglia, this reactive astrocyte expression pattern was enhanced. Thus, after prion infection, microglia appeared to decrease the overall A1/A2-astrocyte responses which might contribute to increased survival after infection.

Itemization of the GO


Biological Processes that were statistically enriched when comparing RML-infected mice to Uninfected mice by RNA-seq at 80, 100, and ~ 157 dpi. Few GO biological categories were affected at 80 dpi, but evidence of dysregulation in more biological processes was apparent as prion disease progressed. The affected categories are indicated with the number of genes that were differential expressed that are associated with that specific biological process in parentheses. Not all enriched biological processes could be included for 100 dpi and ~ 157 dpi but can be found in Additional File, Supplementary Dataset 3, where a full analysis of GO: Biological Processes, Cellular Component, and Molecular Function and the associated genes can be found

RNA-seq analysis indicated dysregulation of over 300 biological processes within the CNS during prion disease. Distinctive microglia- and astrocyte-associated expression signatures were identified during prion infection. Furthermore, astrogliosis and the unique astrocyte-associated expression signature were independent of microglial influences. Astrogliosis and the unique astrocyte-associated gene expression pattern were increased when microglia were ablated. These findings emphasize the potential existence of alternative pathways for activating the A1/A2 paradigm in astrocytes during neurodegenerative disease.

Carroll JA, Race B, Williams K, Striebel J, Chesebro B. (2020) RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection. Mol Brain 13(1):71. [article]

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