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1.
MicroPubl Biol ; 20242024.
Artigo em Inglês | MEDLINE | ID: mdl-39027732

RESUMO

The transcription factor SKN-1 in Caenorhabditis elegans is a critical regulator of various biological processes, impacting development, diet and immune responses, cellular detoxification, and lipid metabolism; thereby playing a pivotal role in regulating the health and lifespan of the organism. The primary isoforms of SKN-1 ( SKN-1 a, SKN-1 b, and SKN-1 c) exhibit distinct functions resembling mammalian Nrf transcription factors. This study investigates the specific role of the SKN-1 c isoform in development by generating mutants with targeted missense mutations in the skn-1 c and skn-1 a isoforms. The skn-1 c Met1Ala mutants, which replaces a start methionine with alanine, renders SKN-1 c non-functional while preserving other isoforms, produced inviable embryos, requiring a balancer chromosome for proper embryonic development. In contrast, skn-1 a Met1Ala mutants, which replaces the start methionine with alanine for this isoform, displayed normal embryonic development and hatching. Moreover, the data suggest that SKN-1 c plays a crucial role in embryonic development, as strains without maternally deposited SKN-1 c lead to embryos that are developmentally arrested. Together, these findings contribute to our understanding of SKN-1 c's specific role in influencing embryogenesis and development in C. elegans.

2.
bioRxiv ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38854121

RESUMO

The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic and dopaminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while minor, but statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

3.
Front Aging ; 5: 1369740, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38501033

RESUMO

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

4.
Proc Natl Acad Sci U S A ; 120(52): e2308565120, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38113255

RESUMO

Coordination of cellular responses to stress is 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 Caenorhabditis 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 noncoding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a unique 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 effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell nonautonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.


Assuntos
Proteínas de Caenorhabditis elegans , Fatores de Transcrição , Animais , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Estresse Oxidativo/fisiologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Longevidade/genética , Neurônios/metabolismo
5.
bioRxiv ; 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37873147

RESUMO

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 STATEMENT: Unlike 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.

6.
Geroscience ; 45(6): 3359-3370, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37751046

RESUMO

Molecular homeostats play essential roles across all levels of biological organization to ensure a return to normal function after responding to abnormal internal and environmental events. SKN-1 is an evolutionarily conserved cytoprotective transcription factor that is integral for the maintenance of cellular homeostasis upon exposure to a variety of stress conditions. Despite the essentiality of turning on SKN-1/NRF2 in response to exogenous and endogenous stress, animals with chronic activation of SKN-1 display premature loss of health with age, and ultimately, diminished lifespan. Previous genetic models of constitutive SKN-1 activation include gain-of-function alleles of skn-1 and loss-of-function alleles of wdr-23 that impede the turnover of SKN-1 by the ubiquitin proteasome. Here, we define a novel gain-of-function mutation in the xrep-4 locus that results in constitutive activation of SKN-1 in the absence of stress. Although each of these genetic mutations results in continuously unregulated transcriptional output from SKN-1, the physiological consequences of each model on development, stress resistance, reproduction, lipid homeostasis, and lifespan are distinct. Here, we provide a comprehensive assessment of the differential healthspan impacts across multiple models of constitutive SKN-1 activation. Although our results reveal the universal need to reign in the uncontrolled activity of cytoprotective transcription factors, we also define the unique signatures of each model of constitutive SKN-1 activation, which provides innovative solutions for the design of molecular "off-switches" of unregulated transcriptional homeostats.


Assuntos
Proteínas de Caenorhabditis elegans , Proteínas de Ligação a DNA , Animais , Proteínas de Ligação a DNA/genética , Proteínas Repressoras/genética , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Fatores de Transcrição/genética
7.
Neurobiol Dis ; 134: 104627, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31786370

RESUMO

Over 1250 mutations in SCN1A, the Nav1.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEFS+. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies.


Assuntos
Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Neurônios , Genótipo , Humanos , Células-Tronco Pluripotentes Induzidas , Mutação , Fenótipo , Convulsões Febris/genética
8.
Rev. biol. trop ; 62(supl.3): 283-298, Jul.-Sep. 2014. ilus, graf, tab
Artigo em Inglês | LILACS | ID: lil-757332

RESUMO

Coral reefs have largely declined across the northeastern Caribbean following the 2005 massive bleaching event. Climate change-related sea surface warming and coral disease outbreaks of a white plague-like syndrome and of yellow band disease (YBD) have caused significant coral decline affecting massive reef building species (i.e., Orbicella annularis species complex) which show no apparent signs of recovery through larval sexual recruitment. We addressed coral recruit densities across three spur and groove reef locations along the western shelf of remote Mona Island, Puerto Rico: Punta Capitán (PCA), Pasa de Las Carmelitas (PLC), and Las Carmelitas-South (LCS). Data were collected during November 2012 along 93 haphazard transects across three depth zones (<5m, 5-10m, 10-15m). A total of 32 coral species (9 octocorals, 1 hydrocoral, 22 scleractinians) were documented among the recruit community. Communities had low densities and dominance by short-lived brooder species seven years after the 2005 event. Mean coral recruit density ranged from 1.2 to 10.5/m2 at PCA, 6.3 to 7.2/m² at LCS, 4.5 to 9.5/m² at PLC. Differences in coral recruit community structure can be attributed to slight variation in percent macroalgal cover and composition as study sites had nearly similar benthic spatial heterogeneity. Dominance by ephemeral coral species was widespread. Recovery of largely declining massive reef-building species such as the O. annularis species complex was limited or non-existent. The lack of recovery could be the combined result of several mechanisms involving climate change, YBD disease, macroalgae, fishing, urchins and Mona Island’s reefs limited connectivity to other reef systems. There is also for rehabilitation of fish trophic structure, with emphasis in recovering herbivore guilds and depleted populations of D. antillarum. Failing to recognize the importance of ecosystem-based management and resilience rehabilitation may deem remote coral reefs recovery unlikely.


Los arrecifes de coral han disminuido en gran medida en el noreste del Caribe después de los blanqueamientos y muerte masiva de coral en el 2005. El calentamiento superficial del mar relacionado con el cambio climático y brotes de enfermedades en corales como el sindrome de plaga blanca y la enfermedad de banda amarilla (YBD) han causado una disminución significativa de coral de arrecife afectando las especies constructoras de coral (es decir, el complejo de especies Orbicella annularisOrbicella annularis) que no muestran signos evidentes de recuperación a través del reclutamiento larval sexual. Nos centramos en las densidades de coral recluta en tres sitios de coral espuela y surco a lo largo de la plataforma occidental de la remota Isla de Mona, Puerto Rico: Punta Capitán (PCA), Pasa de Las Carmelitas (PLC) y Las Carmelitas-Sur (LCS). Los datos fueron recolectados durante noviembre de 2012 a lo largo de 93 transectos a través de tres zonas de profundidad (<5m, 5-10m, 10-15m). Se documentaron un total de 32 especies de corales (9 octocorales, 1 hidrocoral, 22 scleractinios) entre la comunidad coral recluta. Comunidades de coral recluta mostraron bajas densidades y predominancia por especies criadoras rápidas durante siete años después del evento del 2005. La densidad coral recluta varió entre 1.2 y 10.5/m² en el PCA, 6.3 y 7.2/m² en LCS, 4.5 a 9.5/m² en el PLC. Diferencias en la estructura de la comunidad coral recluta pueden atribuirse a la ligera variación en el porcentaje de cobertura de macroalgas y composición en los sitios de estudio que tenían una heterogeneidad espacial bentónica muy similar. Tendencias en el predominio de las especies de coral efímeras fueron generalizadas. Recuperación de especies de arrecife con alta disminución como la especie O. annularis del complejo de especies fue muy limitado e incluso inexistente a través de zonas extensas de arrecife. La falta de recuperación puede ser el resultado combinado de varios mecanismos que implican cambio climático, brotes crónicos de YBD, macroalgas, pesca, erizos y conectividad limitada de los arrecifes de la isla Mona a otros sistemas de arrecife. También hay una necesidad de impulsar la rehabilitación de la estructura trófica de peces, con énfasis en la recuperación de gremios herbívoros y las poblaciones agotadas de D. antillarum. Al no reconocer la importancia de la gestión de rehabilitación y capacidad de recuperación basado en los ecosistemas se estima que la recuperación de arrecifes de coral es muy improbable.

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