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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. and Partridge, Linda 2021. Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system. Proceedings of the National Academy of Sciences 118 (8) , e2011491118. 10.1073/pnas.2011491118

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 1 June 2021
Date of Acceptance: 20 January 2021
Last Modified: 01 Jun 2021 11:36

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