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Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons
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 disease...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531780/ https://www.ncbi.nlm.nih.gov/pubmed/36192034 http://dx.doi.org/10.26508/lsa.202201530 |
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author | Bauer, Susanne Dittrich, Lars Kaczmarczyk, Lech Schleif, Melvin Benfeitas, Rui Jackson, Walker S |
author_facet | Bauer, Susanne Dittrich, Lars Kaczmarczyk, Lech Schleif, Melvin Benfeitas, Rui Jackson, Walker S |
author_sort | Bauer, Susanne |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9531780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-95317802022-10-05 Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons Bauer, Susanne Dittrich, Lars Kaczmarczyk, Lech Schleif, Melvin Benfeitas, Rui Jackson, Walker S Life Sci Alliance Research Articles 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. Life Science Alliance LLC 2022-10-03 /pmc/articles/PMC9531780/ /pubmed/36192034 http://dx.doi.org/10.26508/lsa.202201530 Text en © 2022 Bauer et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Bauer, Susanne Dittrich, Lars Kaczmarczyk, Lech Schleif, Melvin Benfeitas, Rui Jackson, Walker S Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons |
title | Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons |
title_full | Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons |
title_fullStr | Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons |
title_full_unstemmed | Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons |
title_short | Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons |
title_sort | translatome profiling in fatal familial insomnia implicates tor signaling in somatostatin neurons |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531780/ https://www.ncbi.nlm.nih.gov/pubmed/36192034 http://dx.doi.org/10.26508/lsa.202201530 |
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