Mus musculus strain:C57BL/6
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ABSTRACT:
PROVIDER: PRJNA336455 | ENA |
REPOSITORIES: ENA
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Project description:Voluntary running triggers VGF-mediated oligodendrogenesis to prolong the lifespan of Snf2h-null ataxic mice
| PRJNA340987 | ENA
Project description:Exercise enhances cognitive function and slows progressive neurodegenerative disease. While exercise promotes neurogenesis, oligodendrogenesis and adaptive myelination are also significant contributors to brain repair and brain health. Nonetheless, the molecular details underlying these effects remain poorly understood. Conditional ablation of the Snf2h gene (Snf2h cKO) impairs cerebellar development producing mice with poor motor function, progressive ataxia and death between postnatal day 25 to 45. Here we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in hindbrain myelination and the long-term survival of Snf2h cKO mice. Further experiments identified the VGF growth factor as a major driver underlying this effect. VGF neuropeptides could promote oligodendrogenesis in vitro, while Snf2h cKO mice treated with full-length VGF-encoding adenoviruses obliterated the requirement of exercise for survival. Together, these results suggest that VGF delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the central nervous system.
2016-08-31 | GSE86235 | GEO
Project description:The neuropeptide VGF was recently proposed as a neurodegeneration biomarker. The Parkinson's disease-related protein leucine-rich repeat kinase 2 (LRRK2) regulates endolysosomal dynamics, a process that involves SNARE-mediated membrane fusion and could regulate secretion. Here we investigate potential biochemical and functional links between LRRK2 and v-SNAREs. We find that LRRK2 directly interacts with the v-SNAREs VAMP4 and VAMP7. Secretomics reveals VGF secretory defects in VAMP4 and VAMP7 knockout (KO) neuronal cells. In contrast, VAMP2 KO "regulated secretion-null" and ATG5 KO "autophagy-null" cells release more VGF. VGF is partially associated with extracellular vesicles and LAMP1+ endolysosomes. LRRK2 expression increases VGF perinuclear localization and impairs its secretion. Retention using selective hooks (RUSH) assays show that a pool of VGF traffics through VAMP4+ and VAMP7+ compartments, and LRRK2 expression delays its transport to the cell periphery. Overexpression of LRRK2 or VAMP7-longin domain impairs VGF peripheral localization in primary cultured neurons. Altogether, our results suggest that LRRK2 might regulate VGF secretion via interaction with VAMP4 and VAMP7.
2023-01-31 | PXD028321 | Pride
Project description:Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health 1. The natural polyamine spermidine has been linked to autophagy regulation, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders 2. Here, we report that spermidine levels increase upon acute fasting in yeast, flies, mice and healthy humans. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, worms and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan-extending, cardioprotective and antiarthritic effects of intermittent fasting. Mechanistically, spermidine mediated these effects via hypusination of the autophagy regulator eIF5A. In sum, the polyamine-hypusination axis thus emerges as a bona fide and phylogenetically conserved metabolic control hub for longevity and autophagy induction.
2024-04-30 | PXD035909 | Pride
Project description:This study investigates the transcriptional changes induced by VGF overexpression in A549 and H1299 NSCLC cell lines. RNA-seq was performed on cells transfected with a VGF lentivirus or an empty vector control. The goal is to identify dysregulated genes and pathways mediated by VGF overexpression in lung cancer cells.
2025-08-04 | GSE303988 | GEO
Project description:Methionine restriction (MR) extends the lifespan and healthspan of numerous eukaryotic organisms, but the molecular mechanisms at play are unclear. Here we find that the ability of MR to extend the budding yeast chronological and replicative lifespans is the consequence of reduced methionine conversion to the methyl donor S-adenosyl methionine (SAM). Mechanistically, the key antiaging methylation event downregulated by MR is a methylation of protein phosphatase 2A (PP2A). In chronological aging cells during MR the Npr2 component of the SEACIT complex is no longer able to be dephosphorylated by unmethylated PP2A, resulting in inhibition of Tor1 and activation of non-nitrogen-starvation (NNS)-induced autophagy. Deletion of genes encoding components of SEACIT or ATG1 (encoding a central player in the initiation of autophagy) blocked the ability of MR to extend lifespan, showing the critical role of the NNS-induced autophagy pathway in lifespan extension by MR. We identify the relevant Npr2 site dephosphorylated by PP2A as serine 362 and show that Npr2 phosphomimetic mutants are sufficient to extend chronological and replicative lifespan. Finally, we discover that MR only during the early stages of chronological aging is sufficient to prolong autophagy and extend lifespan. In addition to elucidating the molecular mechanism of MR-mediated lifespan extension, this study highlights potential therapeutic targets to achieve lifespan and healthspan extension in humans without the challenging long-term dietary changes required to achieve MR.
2026-06-15 | PXD069602 | Pride
Project description:Mild mitochondrial stress can produce positive effects, a phenomenon referred to as \"mitohormesis.\" This process involves activation of signaling pathways such as the mitochondrial unfolded protein response (UPRmt), which helps restore mitochondrial function and has also been linked to improved health and extended lifespan across various model organisms. In C. elegans, mitohormesis can be triggered through several means—including inhibition of the electron transport chain (ETC), reduction in mitochondrial protein translation, or impaired mitochondrial import—all of which can lead to UPRmt-mediated lifespan extension. However, not all triggers of UPRmt result in increased longevity. For instance, while inhibiting ETC complex II strongly activates UPRmt, it has not been associated with lifespan extension. These findings raise the possibility that UPRmt activation alone may not directly promote longevity. In this study, we aim to investigate this complexity by examining how different mitochondrial stressors that induce UPRmt influence the lifespan of C. elegans. We use RNA-sequencing to profile genome-wide transcriptional responses, with the goal of identifying transcriptomic patterns that may clarify the relationship between UPRmt and longevity.
2025-08-31 | E-MTAB-15031 | biostudies-arrayexpress
Project description:Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Male C57BL/6J mice at 4 weeks of age were purchased from Shanghai Animal Co, Ltd. Mice were maintained under a 12-hour dark/light cycle (lights on at 6:30 am) at a temperature of 22 ± 3 °C in accredited animal facilities. Prior to the start of experiment, mice were maintained on a low-fat diet (Research Diets Inc., New Brunswick, NJ) for one week. At the age of 5 weeks, animals were randomly assigned to one of the 6 intervention groups (n = 30 for each group): feeding of a low-fat diet (10% fat, D12450B, Research Diets) ad libitum (LF) or with 30% calorie restriction (LF+CR) or with voluntary running exercise (LF+Ex), feeding of a high-fat diet (60% fat, D12492, Research Diets) ad libitum (HF) or with 30% calorie restriction (HF+CR) or with voluntary running exercise (HF+Ex). All mice were housed individually during the study. The daily consumption of food in LF and HF groups was recorded over a week and averaged to determine the amount of food for the following week for the LF+CR and HF+CR groups, respectively. After 1 week acclimation in cage with the locked running wheels, mice in the LF+Ex and HF+Ex groups were allowed free access to a running wheel, and the running distance and time were recorded automatically by the equipment. The hepatic transcriptional level for 3 mice from each intervention group at 62 weeks of age was analyzed using Affymetrix Mouse Genome 430 2.0 Arrays.
2012-03-27 | E-GEOD-36838 | biostudies-arrayexpress
Project description:Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, the telomere integrity is not only determined by telomere length but also by epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between telomere shortening-induced DDR and epigenetic modification in aging is unknown. Here we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs), and prolongs lifespan of late generation of telomerase deficient mice (G3Terc-/-). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin status for DDR signaling transduction through the demethylating of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a restores the heterochromatin compaction in the sub-telomeric regions and thereby ameliorating the DDR initiation at short telomeres of G3Terc-/- ISCs. Treatment with a small molecule inhibitor of BER alleviates DDR and improves the maintenance and function of G3Terc-/- ISCs. Taken together, our study discloses a potential therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modulating molecules.
2018-08-22 | GSE117845 | GEO
Project description:Remyelination is a multistep regenerative process that results in the reformation of myelin sheaths around demyelinated axons and is a critical therapeutic target. Here we show that immediate access to a running wheel following toxin-induced demyelination in mice enhances oligodendrogenesis, myelin thickness, and the proportion of remyelinated axons. RNA-sequencing suggests broad activation of pro-remyelination pathways including phagocytosis by exercise and highlights peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) activation. Our study demonstrates that physical activity is an integrative means to enhance remyelination and details a multimodal mechanism including the pivotal PGC1a-dependent enhancement of myelin thickness.
2018-08-16 | GSE118592 | GEO