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

Bolukbasi, E. et al. (2021) Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system. Proceedings of the National Academy of Sciences of the United States of America, 118(8), e201149111. (doi: 10.1073/pnas.2011491118) (PMID:33593901) (PMCID:PMC7923679)

Abstract

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: Articles
• Additional Information: We gratefully acknowledge Wellcome Trust Strategic Award WT098565/ Z/12/Z (to J.M.T. and L.P.), the Max Planck Society (L.P.), and Alzheimer’s Society Fellowship AS-JF-17b-011 (to N.S.W.) for funding this work.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Woodling, Dr Nathan
• Authors: Bolukbasi, E., Woodling, N. S., Ivanov, D. K., Adcott, J., Foley, A., Rajasingam, A., Gittings, L. M., Aleyakpo, B., Niccoli, T., Thornton, J. M., and Partridge, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490
• Published Online: 15 February 2021
• Copyright Holders: Copyright © 2021 the Author(s)
• First Published: First published in Proceedings of the National Academy of Sciences of the United States of America 118(8): e201149111
• Publisher Policy: Reproduced under a Creative Commons license