Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.
Maria I Lazaro-PenaAdam B CornwellCarlos A Díaz-BalzacRitika DasNicholas MacorettaJuilee ThakarAndrew V SamuelsonPublished in: bioRxiv : the preprint server for biology (2023)
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 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 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. 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.
Keyphrases
- transcription factor
- cerebral ischemia
- protein kinase
- heat shock
- poor prognosis
- gene expression
- oxidative stress
- liver failure
- heat stress
- magnetic resonance
- stem cells
- spinal cord injury
- signaling pathway
- magnetic resonance imaging
- immune response
- machine learning
- cell proliferation
- minimally invasive
- tyrosine kinase
- cell therapy
- computed tomography
- single cell
- subarachnoid hemorrhage
- brain injury
- dna binding
- dna methylation
- big data
- acute respiratory distress syndrome
- dendritic cells
- network analysis