Prions induce minor genome-wide translational changes in neurons compared to glia

Abstract

Prion diseases are caused by PrPSc, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrPSc causes a robust, reproducible and specific disease manifestation. Here we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.

Translational regulation enhances distinction of cell types in the nervous system

“…Due to the size of the fly brain (∼0.5 mm) and intricate intercellular adhesions among neurons and glia (Kremer et al, 2017 ), surgical separation is impractical. We thus biochemically purified ribosome-bound mRNAs through genetic tagging of ribosomes in target cells (Chen and Dickman, 2017 ;Sapkota et al, 2019 ;Scheckel et al, 2020 ;Thomas et al, 2012 ;You et al, 2021 ) and further performed Ribo-seq and RNA-seq. By this comparative transcriptome-translatome analyses, we suggest that differential translational programs enhance the distinction of protein synthesis between neuronal and glial cells.…”

Translational regulation enhances distinction of cell types in the nervous system

“…Due to the size of the fly brain (∼0.5 mm) and intricate intercellular adhesions among neurons and glia (Kremer et al, 2017 ), surgical separation is impractical. We thus biochemically purified ribosome-bound mRNAs through genetic tagging of ribosomes in target cells (Chen and Dickman, 2017 ;Sapkota et al, 2019 ;Scheckel et al, 2020 ;Thomas et al, 2012 ;You et al, 2021 ) and further performed Ribo-seq and RNA-seq. By this comparative transcriptome-translatome analyses, we suggest that differential translational programs enhance the distinction of protein synthesis between neuronal and glial cells.…”