Biology subjects

Stuhr, N.

Publications and source records attributed to Stuhr, N..

4 recordsLinked to original sources

bioRxiv2024

C. elegans display antipathy behavior towards food after contemporaneous integration of nutritional needs and dietary lipid availability

Organisms utilize sophisticated neurocircuitry to select optimal food sources within their environment. Methylobacterium is a lifespan-promoting bacterial diet for C. elegans that drives faster development and longevity, however after ingestion, C. elegans consistently choose any other food option available. A screen for genetic regulators of the avoidance behavior toward Methylobacterium identified the AWB and AWC sensory neurons and the odr-1 guanylate cyclase expressed exclusively in those four ciliated neurons as mediators of the antipathy response. Metabolic profiling of the Methylobacterium diet reveals a macromolecular profile enriched in saturated fats and here we show that C. elegans sense and integrate signals related to the type of ingested lipids that subsequently cues food-related behaviors. Moreover, disruption of endogenous lipid metabolism modifies the intensity of antipathy toward Methylobacterium which suggests that the current state of lipid homeostasis influences food preference. Enhanced expression of the sphingolipid degradation enzyme Saposin/spp-9 enhances antipathy behaviors and activation of the sphingosine rheostat and more specifically modulation of the bioactive lipid mediator sphingosine-1-phosphate (S1P) acts as a signal to promote avoidance of Methylobacterium. Taken together, our work reveals that C. elegans modify food choices contemporaneously based on the availability of dietary lipids and the ability to metabolize dietary lipids. HIGHLIGHTSO_LIUncover new molecular mechanisms underlying the decision matrix an animal uses to choose what foods to eat. C_LIO_LIDefine the molecular mechanisms underlying an antipathy behavioral response toward foods after initial ingestion that contemporaneously integrates dietary needs with nutritional profile. C_LIO_LIODR-1 signaling from AWB and AWC ciliated neurons of the C. elegans nervous system mediate the antipathy response to diet. C_LIO_LIManipulation of sphingosine-1-phosphate (S1P) of the sphingosine rheostat controls the intensity of the antipathy behavioral response. C_LIO_LIModulating antipathy behaviors can impact the magnitude of the lifespan-promoting effects of longevity diets. C_LI

physiology↗

bioRxiv2024

Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy.

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defense capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival. KEY POINTSO_LIIdentify an apathy-like behavioral response for pathogens resulting from the constitutive activation of the cytoprotective transcription factor SKN-1. C_LIO_LIUncover the obligate role for serotonin synthesis in both neuronal and non-neuronal cells for the apathy-like state and ability of serotonin treatment to restore normal behaviors. C_LIO_LICharacterize the timing and tissue specificity of SKN-1 nuclear localization in neurons and intestinal cells in response to pathogen exposure. C_LIO_LIDefine the unique and context-specific transcriptional signatures of animals with constitutive SKN-1 activation when exposed to pathogenic environments. C_LIO_LIReveal necessity for both neuronal and non-neuronal serotonin signaling in host survival from pathogen infection. C_LI

genetics↗

bioRxiv2023

A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons

Coordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons in C. elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1, in the intestine, can oppose the e2ffects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system. SIGNIFICANCE STATEMENTUnlike activation, an understudied fundamental question across biological systems is how to deactivate a pathway, process, or enzyme after it has been turned on. The irony that the activation of a transcription factor that is meant to be protective can diminish health was first documented by us at the organismal level over a decade ago, but it has long been appreciated that chronic activation of the human ortholog of SKN-1, NRF2, could lead to chemo- and radiation resistance in cancer cells. A colloquial analogy to this biological idea is a sink faucet that has an on valve without a mechanism to shut the water off, which will cause the sink to overflow. Here, we define this off valve.

genetics↗

bioRxiv2021

Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1-4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5-7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

genetics↗