Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons

  1. Maria I Lazaro-Pena
  2. Adam B Cornwell
  3. Carlos A Diaz-Balzac
  4. Ritika Das
  5. Zachary C Ward
  6. Nicholas Macoretta
  7. Juilee Thakar
  8. Andrew V Samuelson  Is a corresponding author
  1. University of Rochester Medical Center, United States
  2. University of Rochester, United States

Abstract

Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and GABAergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.

Data availability

Our primary sequence data is available for review (GEO accession GSE220744: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE220744). THE TOKEN FOR REVIEWER ACCESS IS:mzaxakemftsplqvData analysis scripts have been deposited at: https://github.com/samuelsonlab-urmc/hpk1_manuscript_2023All data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for all Figures and Figure supplements in 14 Supplementary Files.

The following data sets were generated

Article and author information

Author details

  1. Maria I Lazaro-Pena

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3061-8835
  2. Adam B Cornwell

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0572-3107
  3. Carlos A Diaz-Balzac

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4723-1282
  4. Ritika Das

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zachary C Ward

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicholas Macoretta

    Department of Biology, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Juilee Thakar

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrew V Samuelson

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    For correspondence
    Andrew_Samuelson@URMC.Rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3071-5766

Funding

National Institutes of Health (RF1AG062593)

  • Maria I Lazaro-Pena
  • Adam B Cornwell
  • Ritika Das
  • Zachary C Ward
  • Nicholas Macoretta
  • Andrew V Samuelson

National Institutes of Health (F32HD105323)

  • Carlos A Diaz-Balzac

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Paschalis Kratsios, University of Chicago, United States

Version history

  1. Received: December 23, 2022
  2. Preprint posted: January 12, 2023 (view preprint)
  3. Accepted: June 19, 2023
  4. Accepted Manuscript published: June 20, 2023 (version 1)
  5. Accepted Manuscript updated: June 23, 2023 (version 2)
  6. Version of Record published: August 1, 2023 (version 3)

Copyright

© 2023, Lazaro-Pena et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Maria I Lazaro-Pena
  2. Adam B Cornwell
  3. Carlos A Diaz-Balzac
  4. Ritika Das
  5. Zachary C Ward
  6. Nicholas Macoretta
  7. Juilee Thakar
  8. Andrew V Samuelson
(2023)
Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons
eLife 12:e85792.
https://doi.org/10.7554/eLife.85792

Share this article

https://doi.org/10.7554/eLife.85792

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