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Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system

Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different t...

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Autores principales: Bolukbasi, Ekin, Woodling, Nathaniel S., Ivanov, Dobril K., Adcott, Jennifer, Foley, Andrea, Rajasingam, Arjunan, Gittings, Lauren M., Aleyakpo, Benjamin, Niccoli, Teresa, Thornton, Janet M., Partridge, Linda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923679/
https://www.ncbi.nlm.nih.gov/pubmed/33593901
http://dx.doi.org/10.1073/pnas.2011491118
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author Bolukbasi, Ekin
Woodling, Nathaniel S.
Ivanov, Dobril K.
Adcott, Jennifer
Foley, Andrea
Rajasingam, Arjunan
Gittings, Lauren M.
Aleyakpo, Benjamin
Niccoli, Teresa
Thornton, Janet M.
Partridge, Linda
author_facet Bolukbasi, Ekin
Woodling, Nathaniel S.
Ivanov, Dobril K.
Adcott, Jennifer
Foley, Andrea
Rajasingam, Arjunan
Gittings, Lauren M.
Aleyakpo, Benjamin
Niccoli, Teresa
Thornton, Janet M.
Partridge, Linda
author_sort Bolukbasi, Ekin
collection PubMed
description Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila. Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer’s disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.
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spelling pubmed-79236792021-03-10 Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system Bolukbasi, Ekin Woodling, Nathaniel S. Ivanov, Dobril K. Adcott, Jennifer Foley, Andrea Rajasingam, Arjunan Gittings, Lauren M. Aleyakpo, Benjamin Niccoli, Teresa Thornton, Janet M. Partridge, Linda Proc Natl Acad Sci U S A Biological Sciences Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila. Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer’s disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age. National Academy of Sciences 2021-02-23 2021-02-15 /pmc/articles/PMC7923679/ /pubmed/33593901 http://dx.doi.org/10.1073/pnas.2011491118 Text en Copyright © 2021 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Bolukbasi, Ekin
Woodling, Nathaniel S.
Ivanov, Dobril K.
Adcott, Jennifer
Foley, Andrea
Rajasingam, Arjunan
Gittings, Lauren M.
Aleyakpo, Benjamin
Niccoli, Teresa
Thornton, Janet M.
Partridge, Linda
Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
title Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
title_full Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
title_fullStr Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
title_full_unstemmed Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
title_short Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
title_sort cell type-specific modulation of healthspan by forkhead family transcription factors in the nervous system
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923679/
https://www.ncbi.nlm.nih.gov/pubmed/33593901
http://dx.doi.org/10.1073/pnas.2011491118
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