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Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice.
PLoS Pathog. 18:e1010747 (2022)
Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite appearing normal. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated reduced synthesis of ribosomal and mitochondrial components, 2) glutamatergic neurons showed increased expression of cytoskeletal genes, and 3) GABAergic neurons revealed reduced expression of circadian rhythm genes. These data demonstrate that early translatome responses to neurodegeneration emerge prior to conventional markers of disease and are cell type-specific. Therapeutic strategies may need to target multiple pathways in specific populations of cells, early in disease.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Protein-synthesis Machinery; Selective Vulnerability; Gabaergic Neurons; Prion Diseases; Messenger-rna; Expression; Sleep; Activation; Ribosomes; Mitochondrial
ISSN (print) / ISBN
1553-7366
e-ISSN
1553-7374
Journal
PLoS Pathogens
Quellenangaben
Volume: 18,
Issue: 8,
Article Number: e1010747
Publisher
Public Library of Science (PLoS)
Publishing Place
1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Neurogenomics (ING)
Grants
Deutsches Zentrum für Neurodegenerative Erkrankungen
Knut och Alice Wallenbergs Stiftelse
Deutsche Forschungsgemeinschaft
Swedish National Infrastructure for Computing
Helmholtz-Alberta Initiative-Neurodegenerative Disease Research
Knut och Alice Wallenbergs Stiftelse
Deutsche Forschungsgemeinschaft
Swedish National Infrastructure for Computing
Helmholtz-Alberta Initiative-Neurodegenerative Disease Research