FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science, c2005-
    • Subject Terms:
      Adult Stem Cells/*cytology ; Adult Stem Cells/*metabolism ; Forkhead Box Protein O3/*metabolism ; Neural Stem Cells/*cytology ; Neural Stem Cells/*metabolism; Animals ; Autophagy/genetics ; Autophagy/physiology ; Cells, Cultured ; Forkhead Box Protein O3/antagonists & inhibitors ; Forkhead Box Protein O3/genetics ; Gene Knockout Techniques ; Gene Regulatory Networks ; Mice ; Neurogenesis/genetics ; Neurogenesis/physiology ; Protein Aggregates/genetics ; Protein Aggregates/physiology ; Proteome/genetics ; Proteome/metabolism ; Proteostasis/genetics ; Proteostasis/physiology
    • Abstract:
      Maintenance of a healthy proteome is essential for cellular homeostasis and loss of proteostasis is associated with tissue dysfunction and neurodegenerative disease. The mechanisms that support proteostasis in healthy cells and how they become defective during aging or in disease states are not fully understood. Here, we investigate the transcriptional programs that are essential for neural stem and progenitor cell (NSPC) function and uncover a program of autophagy genes under the control of the transcription factor FOXO3. Using genomic approaches, we observe that FOXO3 directly binds a network of target genes in adult NSPCs that are involved in autophagy, and find that FOXO3 functionally regulates induction of autophagy in these cells. Interestingly, in the absence of FOXO activity, aggregates accumulate in NSPCs, and this effect is reversed by TOR (target of rapamycin) inhibition. Surprisingly, enhancing FOXO3 causes nucleation of protein aggregates, but does not increase their degradation. The work presented here identifies a genomic network under the direct control of a key transcriptional regulator of aging that is critical for maintaining a healthy mammalian stem cell pool to support lifelong neurogenesis.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Grant Information:
      R01 AG053268 United States AG NIA NIH HHS; R01 DA053288 United States DA NIDA NIH HHS; T32 MH020068 United States MH NIMH NIH HHS; R01 AG032088 United States AG NIA NIH HHS
    • Accession Number:
      0 (Forkhead Box Protein O3)
      0 (FoxO3 protein, mouse)
      0 (Protein Aggregates)
      0 (Proteome)
    • Publication Date:
      Date Created: 20190412 Date Completed: 20190508 Latest Revision: 20240413
    • Publication Date:
      20240413
    • Accession Number:
      PMC6478346
    • Accession Number:
      10.1371/journal.pgen.1008097
    • Accession Number:
      30973875