Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons

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.

The degree of astrocyte activation is predictive of the incubation time to prion disease

“…In the current work, a number of A1-, A2- and pan-reactive markers were upregulated, where the level of upregulation within each group correlated strongly with the incubation times (R 2 = 0.85 for A1-, R 2 = 0.71 for A2- and R 2 = 0.83 for pan-reactive markers). These results are in agreement with previous studies [ 12 , 13 , 16 , 19 , 44 ] and illustrate that in prion diseases, astrocytes do not follow the simple A1/A2 polarization model. The concept for polarization into A1 or A2 states was developed using animals treated with LPS or subjected to ischemia (MCAO), conditions that did not induce sustainable, chronic effects [ 58 ].…”

“…Analysis of hippocampal proteome revealed a predominant astrocytic signature in prion-infected mice [ 43 ]. With a growing appreciation of the role of astrocytes in neurodegenerative diseases, the questions whether astrocytes lose their ability to perform normal physiological functions in the reactive states and whether the reactive phenotypes are neurotoxic or neuroprotective still remain unsettled [ 2 , 12 , 43 , 44 ]. These questions are closely related to another important query—do astrocytes simply respond to altered brain homeostasis or, on the contrary, drive pathogenesis?…”

Glial activation in prion diseases is strictly nonautonomous and requires neuronal PrPSc

“…Instead, suppression of neuronal transcripts was only observed at the terminal stage of disease (Sorce et al, 2020). The onset of changes associated with actively translating genes during the course of prion infection also revealed glial perturbation as the major contributors in driving the course of prion disease (Scheckel et al, 2020). More importantly, disease associated microglia (DAM) genes and A1 astrocytes, both of which are renowned glia signatures in several neurodegenerative diseases were upregulated in prion disease.…”

“…Transcriptomic analysis performed in prion-infected mice over the course of disease have revealed dramatic aberrations of glia-enriched genes coinciding with the onset of clinical signs, whereas neuronal changes were less pronounced and were only detected at the terminal stage of the disease (Sorce et al, 2020). Similarly, a quantitative analysis of mRNA translation during the course of prion diseases has found that almost all changes during the progression of prion disease occur in non-neuronal cells, except very late in disease (Scheckel et al, 2020). These findings suggest that it is the glia which experiences initial dysfunction, whereas the neuronal demise is a consequence thereof.…”

Neuroinflammation in Prion Disease

“…Cell type-specific and genome-wide ribosome profiling of prion-infected mouse brains revealed that terminally sick mice with severe neurological symptoms displayed extensive molecular alterations in microglia and astrocytes, whereas only minor changes were detected in translational profiles of neurons. These results again imply that aberrant phenotype of glia suffice to cause disease and may even be the primary driver of prion-induced neurodegeneration [ 40 ].…”