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

Author:

Bauer Susanne1ORCID,Dittrich Lars2,Kaczmarczyk Lech12ORCID,Schleif Melvin2,Benfeitas Rui3,Jackson Walker S12ORCID

Affiliation:

1. Department of Biomedical and Clinical Sciences, Wallenberg Center for Molecular Medicine, Linköping University, Linköping, Sweden

2. German Center for Neurodegenerative Diseases, Bonn, Germany

3. Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Stockholm University, Stockholm, Sweden

Abstract

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 thePrnpgene 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.

Funder

Swedish Research Council

National Bioinformatics Infrastructure Sweden

Knut and Alice Wallenberg

German Center for Neurodegenerative Diseases

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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