Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons.

Bauer S, Dittrich L, Kaczmarczyk L, Schleif M, Benfeitas R, Jackson WS

Life Sci. Alliance 5 (11) - [2022-11-00; online 2022-10-03]

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 <i>Prnp</i> 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.

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PubMed 36192034

DOI 10.26508/lsa.202201530

Crossref 10.26508/lsa.202201530

pmc: PMC9531780
pii: 5/11/e202201530