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

Document Type

Article

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 Starting from published single-cell transcriptomic data, we report that (FKH) is endogenously expressed in neurons, whereas (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 , 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.

Keywords

Alzheimer’s disease, aging, glia, neurons, transcription factors

Medical Subject Headings

Animals; Drosophila Proteins (genetics, metabolism); Drosophila melanogaster (genetics, growth & development, metabolism); Female; Forkhead Transcription Factors (genetics, metabolism); Gene Expression Profiling; Gene Expression Regulation, Developmental; Longevity; Male; Neuroglia (cytology, metabolism); Neurons (cytology, metabolism); Transcriptome

Publication Date

2-23-2021

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

E-ISSN

1091-6490

Volume

118

Issue

8

PubMed ID

33593901

Digital Object Identifier (DOI)

10.1073/pnas.2011491118

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