Loss of region-specific glial homeostatic signature in prion diseases

Abstract

13Background Chronic neuroinflammation is recognized as a major neuropathological hallmark in 14 a broad spectrum of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal 15 Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and 16 astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic 17 neurodegeneration, transform into reactive phenotypes in a region-and disease-specific manner. 18 Little is known about region-specific identity of glia in prion diseases. The current study was 19 designed to determine whether the region-specific homeostatic signature of glia changes with the 20 progression of prion diseases, and whether these changes occur in a region-dependent or universal 21 manner. Also of interest was whether different prion strains give rise to different reactive 22 phenotypes.23 Methods To answer these questions, we analyzed gene expression in thalamus, cortex, 24 hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using Nanostring 25 Neuroinflammation panel at subclinical, early clinical and advanced stages of the disease. 26 ResultsWe found that at the preclinical stage of the disease, region-specific homeostatic identities 27 were preserved. However, with the appearance of clinical signs, region-specific signatures were 28 partially lost and replaced with a neuroinflammation signature. While the same sets of genes were 29 activated by both prion strains, the timing of neuroinflammation and the degree of activation in 30 different brain regions was strain-specific. Changes in astrocyte function scored at the top of 31 activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway 32 responded to prion infection prior to activated microglia or neuron and neurotransmission 33 pathways. 34Conclusions The current work established neuroinflammation gene expression signature 35 associated with prion diseases. Our results illustrate that with the disease progression, the region-36 specific homeostatic transcriptome signatures are replaced by region-independent 37 neuroinflammation signature, which was common for prion strains with different cell tropism. The 38 prion-associated neuroinflammation signature identified in the current study overlapped only 39 partially with the microglia degenerative phenotype and the disease-associated microglia 40 phenotype reported for animal models of other neurodegenerative diseases. 41 3 Background 45 Chronic neuroinflammation is recognized as one of the major neuropathological hallmarks 46 of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia, 47 Amyotrophic Lateral Sclerosis, and prion diseases [1]. Chronic neuroinflammation manifests itself 48 as a sustained activation of glial cells and the transformation of their homeostatic phenotype into 49 reactive phenotypes [2, 3]. Transcriptome analysis and single-cell RNA-sequencing revealed 50 considerable region-specific homeosta...

Region-Specific Sialylation Pattern of Prion Strains Provides Novel Insight into Prion Neurotropism

“…In 22L-infected animals, the thalamus display prion deposition and chronic neuroinflammation prior to cortex and hippocampus [7,74]. Moreover, by the terminal stage of the disease, the thalamus is affected more severely than other brain regions [7,74]. In mice, high vulnerability of thalamus to prion infection was found to be irrespective of a prion strain [7,12,66,74,75].…”

“…In 22L-infected animals, the thalamus display prion deposition and chronic neuroinflammation prior to cortex and hippocampus [7,74]. Moreover, by the terminal stage of the disease, the thalamus is affected more severely than other brain regions [7,74].…”

“…Moreover, by the terminal stage of the disease, the thalamus is affected more severely than other brain regions [7,74]. In mice, high vulnerability of thalamus to prion infection was found to be irrespective of a prion strain [7,12,66,74,75]. What, then, makes the thalamus so vulnerability to prion invasion and chronic neuroinflammation?…”

Deficiency in ST6GAL1, one of the two α2,6-sialyltransferases, has only a minor effect on the pathogenesis of prion disease

“…Consistent with this hypothesis is a correlation between the region-specific sialylation status of PrP Sc and the vulnerability of brain regions to prion infection (Makarava et al, 2020a). The thalamus displays prion deposition and chronic neuroinflammation prior to cortex and hippocampus and, by the terminal stage of the disease, the thalamus is affected more severely than any other brain region (Karapetyan et al, 2009;Sandberg et al, 2014;Carroll et al, 2016;Makarava et al, 2019;Makarava et al, 2020b;Makarava et al, 2021). Regardless of prion strain, thalamic PrP Sc is sialylated less than cortex and hippocampus PrP Sc (Makarava et al, 2020a).…”

Endoplasmic reticulum stress and ubiquitin-proteasome system impairment in natural scrapie

“…Other authors did not find an upregulation of this gene in thalamic neurons in prion-infected mice (Tanaka et al, 2020). Studies in prion disease models suggest that the thalamus displays prion deposition prior to cortex and hippocampus and is affected more severely than other brain regions (Carroll et al, 2016;Makarava et al, 2020).…”