Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons
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ABSTRACT:
PROVIDER: PRJNA911265 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22686273.fastq.gz | Fastqsanger.gz | |||
| SRR22686274.fastq.gz | Fastqsanger.gz | |||
| SRR22686275.fastq.gz | Fastqsanger.gz | |||
| SRR22686276.fastq.gz | Fastqsanger.gz | |||
| SRR22686277.fastq.gz | Fastqsanger.gz |
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Project description: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.
2023-07-28 | GSE220744 | GEO
Project description: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 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 that 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 γ-aminobutyric acid (GABA)ergic 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.
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Project description: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.
2024-06-15 | E-MTAB-14132 | biostudies-arrayexpress
Project description:Human serotonergic neurons are derived using published transdifferentiation protocols. Human Fibroblasts correspond to human fibroblasts (from Line#1, Coriell bought (AG08498)). Samples labeled human neurons or induced neurons (iN) correspond to neurons transdifferentiated from fibroblasts using two transcription factors, as previously described (#1-AG08498 or #2:ERF-1, Erlangen Germany, a line given to us by collaborators) into primarily glutamatergic neruons. Samples labled 5-HT neurons or serotonergic neurons or iSN correspond to serotonergic neurons derived from the stated fibroblast lines, using an additional four transcription factors. For transdifferentiation of iN and iSN, fibroblasts were made to overexpress the stated transcription factors in a doxycycline inducible manner for up to 3 weeks, and then neurons are sorted out and collected directly into Trizol for RNA preparation and sequencing. The non-transdifferentiated fibroblast lines were collected in bulk withtout differentiation into neurons. The line number corresponds to the same fibroblast line either being transdifferentiated into iN or iSN, as labeled - for direct and groupwise comparison.
2016-02-02 | E-MTAB-3680 | biostudies-arrayexpress
Project description:The Dlx homeodomain transcription factors are implicated in regulating the function of inhibitory GABAergic interneurons; therefore understanding their functions will provide insights into disorders such as epilepsy, mental retardation and autism. Identifying genes that are downstream of Dlx1/2 function and are relevant for the differentiation and survival of GABAergic interneurons. During embryonic development, cortical GABAergic interneurons are generated in the proliferative zone of the medial ganglionic eminence (MGE), from where they migrate to reach their final positions in the cortex. The differentiation of these interneuron precursors is dependent on Dlx genes, as shown by Dlx1/Dlx2 double mutants, which have a block in GABAergic cell differentiation and in cell migration. When interneuron progenitors are isolated from the mutant MGE and growth in culture, they are able to proceed along their differentiation program. However, mutant cells growth in vitro show defects in cell morphogenesis and increased cell apoptosis. We hypothesize that Dlx transcription factors regulate important aspects of GABAergic neuron differentiation such as the formation and growth of axon and dendrites, and the formation of inhibitory synapses. We generated E15.5 mouse embryos that are Dlx1/2 -/- or Dlx1/2 +/?. Genotype was confirmed by PCR. A total of 8 litters were used. For each experiment, we pooled tissue from at least 6 different embryos of the same genotype. We dissected the ventricular and subventricular zones of the MGE (rostral part). This area contains ~1 million of progenitor cells per embryo. We isolated total RNA using the Stratagene RNA Miniprep kit (these samples are called MGE+/ and MGE-/- in our proposal). In addition, we used the same area (ventricular and subventricular zones of the rostral MGE) to perform primary neuronal cultures. Cells were maintained 3 days in vitro. After that, we isolated total RNA using the Stratagene RNA Miniprep kit (samples called primary cells+/ and primary cells-/- in our proposal). We would like to perform gene expression comparison between: 1) MGE+/ and MGE-/-, and 2) primary cells+/ and primary cells-/-. Keywords: Dlx mutants, medial ganglionic eminence, neuronal cultures
2007-06-27 | GSE8311 | GEO
Project description:The goals of this study were to study serotonergic neuron differentiation from patient derived iPSCs
2019-01-03 | GSE117910 | GEO
Project description:Performed RNA-seq analysis of animals with xbp-1s overexpression (ER stress response transcription factor) in specific neuron types: pan-neuronal, serotonergic neuron, dopaminergic neuron, and both serotonergic and dopaminergic neurons, all compared to a wild-type control. RNA-seq was performed on purified RNA extracted from ~1000 whole worms using a proprietary Genewiz protocol described briefly in the manuscript. 3 biological replicates are provided for each sample.
2021-01-01 | E-MTAB-9771 | biostudies-arrayexpress
Project description:Serotonin regulates its own production, degradation and release in the Raphe nuclei of the brain mainly by modifying the level and activity of autoreceptors on serotonin-producing neurons, such as 5-HT1A and 5-HT1B. This autoregulation is probably the reason for the delayed response of patients with depression to the most common antidepressive drugs inhibiting the serotonin transporter (SERT), a molecule responsible for the reuptake of serotonin and therefore for its quick removal from the synaptic cleft. However, the signaling pathways involved in autoregulation and the molecular alterations induced by serotonin on its autoreceptors are yet unclear. We aim at analysing changes in levels of proteins induced by longterm changes of serotonin levels in Raphe nuclei of mice with low and elevated serotonin release in the brain to reveal the signaling pathways involved in the autoregulation of serotonergic neurons.
2025-05-07 | PXD055579 | Pride
Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
2015-12-15 | E-GEOD-74065 | biostudies-arrayexpress
Project description:Transcriptional profiling of isolated homeodomain 2 (hd2) trichomes
2009-02-04 | E-MEXP-2022 | biostudies-arrayexpress