CoChat
Sign Up
PreprintCited by 11Genetics, Aging, and Longevity in Model OrganismsNeurobiology and Insect Physiology ResearchAutophagy in Disease and Therapy

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

Open access
Lazaro-Pena, Maria I., Cornwell, Adam B., Diaz-Balzac, Carlos A., Das, Ritika, Ward, Zachary C., Macoretta, Nicholas, Thakar, Juilee, Samuelson, Andrew V.·2023·eLife
DOI 10.1101/2023.01.11.523661PMC PMC10393298

Preprint — published as 10.7554/elife.85792 · Paper page

Open this paper in CoChat — free account

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 h omeodomain-interacting p rotein k inase (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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2023.01.11.523661

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 172

  1. 10.1016/S0896-6273(03)00816-X · DOI · Paper page
  2. 10.1101/gad.1107803 · DOI
  3. 10.1038/45544 · DOI · Paper page
  4. 2013, Alzheimer’s disease: an update of the roles of receptors, astrocytes and primary cilia (review), International journal of molecular medicine, 31, 3, 10.3892/ijmm.2012.1162 · DOI
  5. 10.1126/science.1141448 · DOI · Paper page
  6. 2017, Hyperglycemia triggers HIPK2 protein degradation, Oncotarget, 8, 1190, 10.18632/oncotarget.13595 · DOI
  7. 2013, Homeodomain interacting protein kinase (HPK-1) is required in the soma for robust germline proliferation in C. elegans, Developmental dynamics : an official publication of the American Association of Anatomists, 242, 1250, 10.1002/dvdy.24023 · DOI
  8. 2016, Homeodomain-Interacting Protein Kinase (HPK-1) regulates stress responses and ageing in C. elegans, Scientific reports, 6, 19582, 10.1038/srep19582 · DOI
  9. 10.1016/j.cell.2016.08.042 · DOI
  10. 10.1534/genetics.119.302504 · DOI
  11. 10.1016/bs.ctdb.2016.10.002 · DOI
  12. 10.1093/bioinformatics/btu170 · DOI · Paper page
  13. 10.1523/JNEUROSCI.0990-06.2006 · DOI
  14. 10.4161/cc.6.2.3788 · DOI
  15. 10.1016/j.bbrc.2012.09.056 · DOI · Paper page
  16. 10.1371/journal.pgen.1000486 · DOI · Paper page
  17. 2018, Neuropeptides Exert Neuroprotective Effects in Alzheimer’s Disease, Front Mol Neurosci, 11, 493
  18. 1986, Mitochondrial function and intracellular calcium in anoxic cardiac myocytes, The American journal of physiology, 250, C18, 10.1152/ajpcell.1986.250.1.C18 · DOI
  19. 2015, Metabotropic GABA signalling modulates longevity in C. elegans, Nature communications, 6, 8828, 10.1038/ncomms9828 · DOI
  20. 10.1016/j.cub.2005.02.025 · DOI
  21. Cornwell, A.B. , Llop, J.R. , Salzman, P. , Thakar, J. , and Samuelson, A.V . (2018). The Replica Set Method: A High-throughput Approach to Quantitatively Measure Caenorhabditis elegans Lifespan. Journal of visualized experiments : JoVE. · DOI
  22. 10.1093/NAR/GKAB1049 · DOI · Paper page
  23. 10.1371/journal.pgen.1007038 · DOI
  24. 10.1016/j.molcel.2012.03.003 · DOI
  25. 10.1016/j.febslet.2004.07.006 · DOI
  26. 10.1093/gerona/glu061 · DOI
  27. 2002, Pymol: An open-source molecular graphics tool, CCP4 Newsl Protein Crystallogr, 40, 82
  28. 10.1016/j.mad.2018.08.001 · DOI
  29. 10.1093/bioinformatics/bts635 · DOI · Paper page
  30. 10.1016/j.celrep.2015.07.026 · DOI
  31. 10.1016/j.cell.2010.12.016 · DOI · Paper page
  32. 10.1128/MCB.23.3.950-960.2003 · DOI
  33. 10.7554/eLife.06259 · DOI
  34. 10.1038/nature14021 · DOI
  35. 10.1111/acel.12301 · DOI
  36. 10.1126/science.aaz6896 · DOI
  37. 10.1101/gad.1575307 · DOI
  38. 2013, Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy, Cell death & disease, 4, e639, 10.1038/cddis.2013.163 · DOI
  39. Gendrel, M. , Atlas, E.G. , and Hobert, O . (2016). A cellular and regulatory map of the GABAergic nervous system of C. elegans. Elife 5. · DOI
  40. 10.1126/science.1124514 · DOI · Paper page
  41. 10.1016/j.sbi.2009.11.001 · DOI
  42. 10.1128/MCB.17.4.2301 · DOI
  43. 10.1101/gad.1308205 · DOI
  44. 10.1126/science.1165527 · DOI
  45. 10.1371/journal.pgen.0040024 · DOI · Paper page
  46. 10.1111/j.1474-9726.2006.00267.x · DOI · Paper page
  47. 10.1016/J.CELL.2021.04.048 · DOI · Paper page
  48. 10.1002/neu.10014 · DOI
  49. 10.1093/nar/gkh036 · DOI
  50. 10.1093/NAR/GKZ920 · DOI
  51. Hart, A.C . (2006). Behavior. In The C elegans Research Community, WormBook. · DOI · Paper page
  52. 10.1182/blood-2009-07-235093 · DOI
  53. 2010, Characterization of Human Homeodomain-interacting Protein Kinase 4 (HIPK4) as a Unique Member of the HIPK Family, Molecular and cellular pharmacology, 2, 61
  54. 10.1038/nature01135 · DOI · Paper page
  55. 10.1128/MCB.23.8.2953-2968.2003 · DOI
  56. 10.1073/pnas.0503698102 · DOI
  57. 2020, Divergent Nodes of Non-autonomous UPR(ER) Signaling through Serotonergic and Dopaminergic Neurons, Cell Rep, 33, 108489, 10.1016/j.celrep.2020.108489 · DOI
  58. 10.1101/cshperspect.a019141 · DOI
  59. Hobert, O . (2013). The neuronal genome of Caenorhabditis elegans. WormBook, 1–106. · DOI
  60. 2022, The Intestine as a Lifespan- and Proteostasis-Promoting Signaling Tissue, Front Aging, 3, 897741, 10.3389/fragi.2022.897741 · DOI
  61. 2003, HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells, Cancer Res, 63, 8271
  62. 10.1073/pnas.0400848101 · DOI
  63. 10.1038/s12276-018-0048-7 · DOI
  64. 2021, Author Correction: Single-cell RNA sequencing technologies and bioinformatics pipelines, Experimental & molecular medicine, 53, 1005, 10.1038/s12276-021-00615-w · DOI
  65. 2019, Neuronal XBP-1 Activates Intestinal Lysosomes to Improve Proteostasis in C. elegans, Curr Biol, 29, 2322, 10.1016/j.cub.2019.06.031 · DOI
  66. 10.1007/s00125-014-3257-1 · DOI
  67. 10.1093/nar/gkz1031 · DOI
  68. 10.1038/372780a0 · DOI
  69. 10.1371/journal.pgen.1004278 · DOI
  70. Jorgensen, E.M. , and Nonet, M.L . (1995). Neuromuscular junctions in the nematode C. elegans. Paper presented at: seminars in DEVELOPMENTAL BIOLOGY (Elsevier). · DOI
  71. 2018, Transcriptome analysis of adult Caenorhabditis elegans cells reveals tissue-specific gene and isoform expression, PLoS Genet, 14, e1007559, 10.1371/journal.pgen.1007559 · DOI
  72. 10.1093/nar/28.1.27 · DOI · Paper page
  73. 2022, Single cell RNA-sequencing: A powerful yet still challenging technology to study cellular heterogeneity, Bioessays, 44, e2200084, 10.1002/bies.202200084 · DOI
  74. 10.1038/366461a0 · DOI · Paper page
  75. 10.1007/978-1-4419-7002-2_11 · DOI
  76. 10.1074/jbc.M507227200 · DOI
  77. 10.1073/pnas.1533448100 · DOI · Paper page
  78. 2017, Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans, Nature communications, 8, 14337, 10.1038/ncomms14337 · DOI · Paper page
  79. 10.1146/annurev-biochem-060614-033955 · DOI · Paper page
  80. 10.1002/emmm.201303356 · DOI · Paper page
  81. 2013, The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans, Nature communications, 4, 2267, 10.1038/ncomms3267 · DOI · Paper page
  82. 10.1080/15548627.2015.1034410 · DOI
  83. Lazaro-Pena, M.I. , Cornwell, A.B. , and Samuelson, A.V . (2021). Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans. Journal of visualized experiments : JoVE. · DOI
  84. Lazaro-Pena, M.I. , Ward, Z.C. , Yang, S. , Strohm, A. , Merrill, A.K. , Soto, C.A. , and Samuelson, A.V . (2022). HSF-1: Guardian of the Proteome Through Integration of Longevity Signals to the Proteostatic Network. Frontiers in Aging 3. · DOI
  85. 10.1111/j.1365-2958.2008.06450.x · DOI
  86. 10.1523/JNEUROSCI.19-01-00159.1999 · DOI
  87. 2016, Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis, Neuron, 91, 41, 10.1016/j.neuron.2016.05.021 · DOI
  88. 2009, Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression, Cell metabolism, 10, 379, 10.1016/j.cmet.2009.10.003 · DOI
  89. 10.1126/science.1083614 · DOI · Paper page
  90. 10.1186/1471-2105-12-323 · DOI · Paper page
  91. 2018, Mutations in the guanylate cyclase gcy-28 neuronally dissociate naive attraction and memory retrieval, The European journal of neuroscience, 48, 3367, 10.1111/ejn.14221 · DOI
  92. 10.1093/bioinformatics/btt656 · DOI · Paper page
  93. 10.1126/science.278.5341.1319 · DOI
  94. 2018, DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity, Nature communications, 9, 4400, 10.1038/s41467-018-06624-0 · DOI
  95. 1999, Patterning of dopaminergic neurotransmitter identity among Caenorhabditis elegans ray sensory neurons by a TGFbeta family signaling pathway and a Hox gene, Development, 126, 5819, 10.1242/dev.126.24.5819 · DOI
  96. 10.1006/meth.2001.1262 · DOI · Paper page
  97. 10.1016/j.cell.2013.05.039 · DOI · Paper page
  98. Love, M.I. , Huber, W. , and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15, 550. · DOI · Paper page
  99. 10.1016/j.nbd.2021.105607 · DOI · Paper page
  100. 2006, Analysis of synaptic transmission in Caenorhabditis elegans using an aldicarb-sensitivity assay, Nature protocols, 1, 1772, 10.1038/nprot.2006.281 · DOI
  101. 10.1371/journal.pone.0003354 · DOI
  102. 10.1038/364334a0 · DOI
  103. Miller, H.A. , Dean, E.S. , Pletcher, S.D. , and Leiser, S.F . (2020). Cell non-autonomous regulation of health and longevity. Elife 9. · DOI · Paper page
  104. 2017, Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer’s Disease, Front Cell Neurosci, 11, 339, 10.3389/fncel.2017.00339 · DOI
  105. 10.1101/sqb.2012.76.010637 · DOI
  106. Morimoto, R.I . (2019). Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease. Cold Spring Harbor perspectives in biology. · DOI
  107. 10.1073/pnas.152161099 · DOI
  108. 10.1091/mbc.E03-07-0532 · DOI
  109. 10.1371/journal.pgen.1006133 · DOI
  110. 10.1111/j.1474-9726.2007.00303.x · DOI
  111. 2016, Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals, Nature communications, 7, 10944, 10.1038/ncomms10944 · DOI
  112. 10.1016/j.ygeno.2021.01.007 · DOI
  113. Nisaa, K. , and Ben-Zvi, A . (2021). Chaperone networks are shaped by cellular differentiation and identity. Trends Cell Biol. · DOI
  114. 10.1523/JNEUROSCI.17-21-08061.1997 · DOI
  115. 10.1093/jac/24.1.23 · DOI
  116. 10.1038/ncb2741 · DOI
  117. 10.1038/40194 · DOI
  118. Oh, K.H. , and Kim, H . (2017). Aldicarb-induced Paralysis Assay to Determine Defects in Synaptic Transmission in Caenorhabditis elegans. Bio Protoc 7. · DOI
  119. 10.1093/genetics/135.2.385 · DOI
  120. 10.1371/journal.pone.0038649 · DOI
  121. Oswal, N. , Martin, O.M.F. , Stroustrup, S. , Matusiak Bruckner, M.A. , and Stroustrup, N. (2021). A Hierarchical Process Model Links Behavioral Aging and Lifespan in C. elegans. bioRxiv, 2021.2003.2031.437415. · DOI
  122. 10.1111/j.1474-9726.2006.00266.x · DOI
  123. 10.1101/gad.12.16.2488 · DOI
  124. 10.1038/nature05991 · DOI
  125. 2019, Neuropeptides in Alzheimer’s Disease: An Update, Current Alzheimer research, 16, 544, 10.2174/1567205016666190503152555 · DOI
  126. 10.1016/j.ydbio.2007.07.034 · DOI
  127. 10.1056/NEJMra0903074 · DOI · Paper page
  128. 10.1126/science.1156093 · DOI
  129. 10.1073/pnas.1106557108 · DOI
  130. 2022, Novel elasticity measurements reveal C. elegans cuticle stiffens with age and in a long-lived mutant, Biophys J, 121, 515, 10.1016/j.bpj.2022.01.013 · DOI
  131. 2003, Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A, Genetics, 163, 571, 10.1093/genetics/163.2.571 · DOI
  132. 10.1038/12160 · DOI
  133. 2014, MDL-1, a growth- and tumor-suppressor, slows aging and prevents germline hyperplasia and hypertrophy in C. elegans, Aging (Albany NY, 6, 98
  134. 2007, HIPK2: a multitalented partner for transcription factors in DNA damage response and development, Biochemistry and cell biology = Biochimie et biologie cellulaire, 85, 411
  135. 10.1016/j.bbamcr.2008.06.006 · DOI
  136. Roux, A.E. , Yuan, H. , Podshivalova, K. , Hendrickson, D. , Kerr, R. , Kenyon, C. , and Kelley, D.R. (2022). The complete cell atlas of an aging multicellular organism. bioRxiv, 2022.2006.2015.496201. · DOI
  137. 10.1083/jcb.201612111 · DOI
  138. 10.1101/gad.1588907 · DOI
  139. 2023, HIPK2 in the physiology of nervous system and its implications in neurological disorders, Biochim Biophys Acta Mol Cell Res, 1870, 119465, 10.1016/j.bbamcr.2023.119465 · DOI
  140. 1989, Pharmacological basis for use of calcium antagonists in hypertension, Magnesium, 8, 253
  141. 2021, The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones, Nature communications, 12, 2180, 10.1038/s41467-021-22369-9 · DOI
  142. 10.1007/s12264-007-0003-4 · DOI
  143. 10.1523/JNEUROSCI.4691-10.2011 · DOI
  144. 2012, Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice, Diabetologia, 55, 3318, 10.1007/s00125-012-2711-1 · DOI
  145. 1989, Calcium and cell death, Magnesium, 8, 223
  146. 10.1038/msb.2011.75 · DOI
  147. 10.1371/journal.pgen.1003711 · DOI
  148. 10.1002/jcb.10541 · DOI
  149. 10.1074/jbc.M213201200 · DOI
  150. 10.1111/imb.12363 · DOI
  151. 2013, The Caenorhabditis elegans Lifespan Machine, Nature methods, 10, 665, 10.1038/nmeth.2475 · DOI
  152. 2022, Gene regulatory network inference in long-lived C. elegans reveals modular properties that are predictive of novel aging genes, iScience, 25, 103663, 10.1016/j.isci.2021.103663 · DOI
  153. 10.1038/35000609 · DOI
  154. 10.1371/journal.pone.0048282 · DOI
  155. 10.1016/j.cub.2014.11.040 · DOI
  156. Taylor, R.C. , and Dillin, A . (2011). Aging as an event of proteostasis collapse. Cold Spring Harbor perspectives in biology 3. · DOI · Paper page
  157. 10.1016/j.cell.2013.05.042 · DOI
  158. 10.1016/j.cell.2021.06.023 · DOI
  159. 10.1016/j.neuron.2008.07.038 · DOI
  160. 10.1093/NAR/GKAB1061 · DOI · Paper page
  161. 10.1371/journal.pbio.1001084 · DOI
  162. 2020, Homeodomain-interacting protein kinase (Hipk) plays roles in nervous system and muscle structure and function, PLoS One, 15, e0221006, 10.1371/journal.pone.0221006 · DOI
  163. 10.1016/j.celrep.2021.109529 · DOI
  164. 10.1186/gb-2010-11-2-r14 · DOI · Paper page
  165. 10.1152/ajpcell.00072.2019 · DOI
  166. 10.1042/BCJ20160991 · DOI
  167. 10.1038/nn1816 · DOI
  168. 10.1523/JNEUROSCI.2017-19.2019 · DOI
  169. 10.1016/j.cell.2018.06.029 · DOI
  170. Zhang, Y. , Lanjuin, A. , Chowdhury, S.R. , Mistry, M. , Silva-Garcia, C.G. , Weir, H.J. , Lee, C.L. , Escoubas, C.C. , Tabakovic, E. , and Mair, W.B . (2019). Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans. Elife 8. · DOI
  171. 10.1371/journal.pone.0006348 · DOI · Paper page
  172. 2021, The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing, Nature communications, 12, 1789, 10.1038/s41467-021-22065-8 · DOI

Metadata

Authors
Lazaro-Pena, M. I., Cornwell, A. B., Diaz-Balzac, C. A., Das, R., Ward, Z. C., Macoretta, N., Thakar, J., & Samuelson, A. V.
Affiliations
  • University of Rochester Medicine (US)
  • University of Rochester (US)
Corresponding author
Samuelson, Andrew V.
ORCID
Venue
eLife
Publisher
openRxiv
Published
2023-01-12
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2023.01.11.523661
PMC
PMC10393298
OpenAlex
W4381308515
Cited by
11
References
1
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 1
FWCI
0.74
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Massachusetts General Hospital
  • University of Pittsburgh
  • University of Rochester
  • Korea Advanced Institute of Science and Technology
  • National Institutes of Health (OD010440, P40OD010440)
  • Medical Center, University of Rochester
  • National Institute on Aging (RF1AG062593)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD105323)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
homeodomain-interacting protein kinase, aging, longevity, neuronal homeostasis, proteostasis, serotonergic neurons, GABAergic neurons, heat shock response, autophagy, stress tolerance, transcriptional regulation, Caenorhabditis elegans, DAF-16, TFEB, MLX

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review