TY  - JOUR
AU  - Bauer, Susanne
AU  - Dittrich, Lars
AU  - Kaczmarczyk, Lech
AU  - Schleif, Melvin
AU  - Benfeitas, Rui
AU  - Jackson, Walker Scot
TI  - Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons.
JO  - Life science alliance
VL  - 5
IS  - 11
SN  - 2575-1077
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2022-01629
SP  - e202201530
PY  - 2022
AB  - Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unexpectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.
KW  - Animals
KW  - Creutzfeldt-Jakob Syndrome: genetics
KW  - Insomnia, Fatal Familial: genetics
KW  - Mice
KW  - Monomeric GTP-Binding Proteins: metabolism
KW  - Neurodegenerative Diseases
KW  - Neurons: metabolism
KW  - Prion Diseases: genetics
KW  - Somatostatin: genetics
KW  - Somatostatin: metabolism
KW  - TOR Serine-Threonine Kinases: genetics
KW  - TOR Serine-Threonine Kinases: metabolism
KW  - Somatostatin (NLM Chemicals)
KW  - TOR Serine-Threonine Kinases (NLM Chemicals)
KW  - Monomeric GTP-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36192034
C2  - pmc:PMC9531780
DO  - DOI:10.26508/lsa.202201530
UR  - https://pub.dzne.de/record/165352
ER  -