Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice
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Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice. / Kaczmarczyk, Lech; Schleif, Melvin; Dittrich, Lars; Williams, Rhiannan H; Koderman, Maruša; Bansal, Vikas; Rajput, Ashish; Schulte, Theresa; Jonson, Maria; Krost, Clemens; Testaquadra, Fabio J; Bonn, Stefan; Jackson, Walker S.
In: PLOS PATHOG, Vol. 18, No. 8, e1010747, 08.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice
AU - Kaczmarczyk, Lech
AU - Schleif, Melvin
AU - Dittrich, Lars
AU - Williams, Rhiannan H
AU - Koderman, Maruša
AU - Bansal, Vikas
AU - Rajput, Ashish
AU - Schulte, Theresa
AU - Jonson, Maria
AU - Krost, Clemens
AU - Testaquadra, Fabio J
AU - Bonn, Stefan
AU - Jackson, Walker S
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
U2 - 10.1371/journal.ppat.1010747
DO - 10.1371/journal.ppat.1010747
M3 - SCORING: Journal article
C2 - 35960762
VL - 18
JO - PLOS PATHOG
JF - PLOS PATHOG
SN - 1553-7366
IS - 8
M1 - e1010747
ER -
