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| Status |
Public on Jul 28, 2023 |
| Title |
Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons |
| Organism |
Caenorhabditis elegans |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 premature upregulation of genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system and in more cell-clusters than any other kinase. Within the aging nervous system, hpk-1 is co-expressed with key longevity transcription factors, including daf-16 (FOXO), hlh-30 (TFEB), skn-1 (Nrf2), and hif-1, 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 divergent 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. Our work establishes hpk-1 as a key neuronal transcriptional regulator that is critical for the preservation of neuronal function during aging and insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.
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| Overall design |
Approximately 3000 total C. elegans hermaphrodite animals of either N2 (WT) or hpk-1 (pk1393) mutants were collected at day 2 of adulthood for RNA isolation from populations that were synchronized at L1 and then treated with FUdR at L4 to prevent formation of progeny. Three biological replicates were prepared for each genotype, each consisting of a separate synchronized population of animals. Libraries for RNA-Seq were prepared and sequenced on a HiSeq2500 in 1x100bp mode at the University of Rochester Genomics Research Center.
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| Web link |
https://elifesciences.org/articles/85792
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| Contributor(s) |
Lazaro-Pena MI, Cornwell AB, Diaz-Balzac CA, Das R, Macoretta N, Thakar J, Samuelson AV |
| Citation(s) |
37338980 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| RF1 AG062593 |
Transcriptional control of proteostasis and aging |
UNIVERSITY OF ROCHESTER |
Andrew Vaughn Samuelson |
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| Submission date |
Dec 12, 2022 |
| Last update date |
Aug 11, 2023 |
| Contact name |
Andrew V Samuelson |
| E-mail(s) |
Andrew_Samuelson@URMC.Rochester.edu
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| Organization name |
University of Rochester Medical Center
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| Department |
Biomedical Genetics
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| Lab |
Samuelson Lab
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| Street address |
601 Elmwood Ave
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| City |
Rochester |
| State/province |
NY |
| ZIP/Postal code |
14642 |
| Country |
USA |
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| Platforms (1) |
| GPL18245 |
Illumina HiSeq 2500 (Caenorhabditis elegans) |
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| Samples (6)
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| GSM6813486 |
hpk-1(pk1393), adult day 2, replicate 1 |
| GSM6813487 |
hpk-1(pk1393), adult day 2, replicate 2 |
| GSM6813488 |
hpk-1(pk1393), adult day 2, replicate 3 |
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| Relations |
| BioProject |
PRJNA911265 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE220744_hpk-1_and_N2_D2_RNA-Seq-_filtered_TPM.txt.gz |
340.1 Kb |
(ftp)(http) |
TXT |
| GSE220744_hpk-1_and_N2_D2_RNA-Seq-_filtered_raw_counts.txt.gz |
289.8 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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