Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells
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ABSTRACT:
PROVIDER: PRJNA767411 | ENA |
REPOSITORIES: ENA
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Project description:Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear conditioning behavior of young and mature adults was also abnormal: KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior
2022-03-29 | GSE185031 | GEO
Project description:Epithelial-to-mesenchymal transition (EMT) gives rise to cells with properties similar to cancer stem cells (CSCs) that drive tumor metastasis. Recently, a screening of a large compound library on a breast EMT model has identified salinomycin, a K+/H+ ionophore, as a highly selective drug towards CSCs. We used the same EMT model to show that salinomycin targets Golgi apparatus. We have performed RNA-seq analysis on HMLE-Twist and HMLE-pBp cells (EMT and non-EMT) that were either mock treated or treated for 24h with micro molar concentration (0.2uM) of salinomycin. Salinomycin induced expression of genes enriched by known ER and Golgi stressors.
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Project description:Salinomycin induces expression of ER and Golgi apparatus related genes in EMT cell model
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Project description:The process of aging is associated with disturbed mineral homeostasis, such as zinc deficiency. Simultaneously, cellular response to external stimuli, including receptor signaling and DNA repair response diminishes, and epigenetic dysregulation occurs. The Golgi apparatus plays various roles in the cell; however, the effect of aging on the morphology and function of the Golgi apparatus and the impact of Golgi senescence in cellular activity remains unknown. In the present study, we found that Golgi stress is associated with senescent cell irresponsiveness to external stimuli. The senescent Golgi was associated with a disassembled microtubule network in the Golgi and perinuclear areas. These effects could be reproduced by disruption of the Golgi-associated microtubules or zinc depletion. To clarify the importance of Golgi-zinc homeostasis in more detail, the implications of the Golgi-zinc transporter ZIP13 were analyzed; Zip13-deficient mice Golgi exhibited morphology similar to that of senescent Golgi. Additionally, fibroblasts from Zip13-deficient mice showed dysregulation of DNA repair and cellular acetylation with downregulated nuclear translocation of p300, HDAC1/2, and p53 proteins, which are reminiscent characteristics of senescent cells. Our findings demonstrate the underlying reason for senescent cell irresponsiveness to various stimuli and highlight the importance of a zinc-rich diet during aging.
2024-08-26 | GSE235450 | GEO
Project description:Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. The Dcx protein plays a key role in neuronal migration, and hippocampal pyramidal neurons in Dcx knockout (KO) mice are disorganized. The single CA3 pyramidal cell layer observed in wild type (WT) is present as two abnormal layers in the KO, and CA3 KO pyramidal neurons are more excitable than WT. Dcx KO mice also exhibit spontaneous epileptic activity originating in the hippocampus. It is unknown however, how hyperexcitability arises and why two CA3 layers are observed. Transcriptome analyses were performed to search for perturbed postnatal gene expression, comparing Dcx KO CA3 pyramidal cell layers with WT. Gene expression changes common to both KO layers indicated mitochondria and Golgi apparatus anomalies, as well as increased cell stress. Intriguingly, gene expression analyses also suggested that the KO layers differ significantly from each other, particularly in terms of maturity. Layer-specific molecular markers and BrdU birthdating to mark the final positions of neurons born at distinct timepoints revealed inverted layering of the CA3 region in Dcx KO animals. Notably, many early-born ‘outer boundary’ neurons are located in an inner position in the Dcx KO CA3, superficial to other pyramidal neurons. This abnormal positioning likely affects cell morphology and connectivity, influencing network function. Dissecting this Dcx KO phenotype sheds light on coordinated developmental mechanisms of neuronal subpopulations, as well as gene expression patterns contributing to a bi-layered malformation associated with epilepsy. Expression profiling by array
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Project description:The cumulative role of cellular organelle’s in shaping the life and function of a cell has been long acknowledged. While each organelle plays a specific role in the growth and development of T cells, numerous studies have thus far focused on targeting mitochondria, endoplasmic reticulum, or lysosome related pathways to improve anti-tumor T cell immune response. Here we highlight the tumor microenvironment (TME) mediated disruption of Golgi architecture and function, termed Golgi stress, contributes to altered redox signaling and affects cell survival. Importantly, the decreased expression if GM130, a marker of Golgi stress and indicating the disruption of Golgi architecture, was reverted upon treatment with hydrogen sulphide (H2S) donor GYY4137, or over expressing cystathionine β-synthase (Cbs), an enzyme involved in biosynthesis of endogenous H2S. Activation and expansion of tumor reactive TCR or chimeric antigen receptor bearing T cells expanded with exogenous H2S promoted stemness, antioxidant capacity and exhibited an increase effector cytokine secretion that correlated to increased protein translation. In in vivo models of melanoma and lymphoma, anti-tumor T cells conditioned ex vivo with exogenous H2S or overexpressing Cbs demonstrated superior tumor control upon ACT. Further, sorting anti- tumor T cells based on Golgi structure and abundance resulted in identification of a Golgihi subset of T cells with a unique metabolic signature, superior fitness, and enhanced anti-tumor capacity. These data suggest that H2S can be used an immunomodulatory agent to enhance the efficacy of ACT, and that the structure and function of the Golgi apparatus is an important feature of T cells that determines their anti-tumor capacity.
2024-11-20 | GSE249287 | GEO
Project description:p38 and JNK are activated in response to acute stress and inflammatory signals. Through modification of a plethora of substrates, these kinases profoundly re-shape cellular physiology for the optimal response to a harmful environment and/or an inflammatory state. Here, we utilized phospho-proteomics to identify several hundred substrates for both kinases. Our results indicate that the scale of signaling from p38 and JNK are of a similar magnitude. Among the many new targets, we highlight the regulation of the transcriptional regulators GIGYF1 and 2 by p38-dependent MK2 phosphorylation and 14-3-3 binding. We also show that the Golgi apparatus contains numerous substrates, and is a major target for regulation by p38 and JNK. When activated, these kinases mediate structural rearrangement of the Golgi apparatus which positively affects protein flux through the secretory system. Our work expands on our knowledge about p38 and JNK signaling with important biological ramifications.
2021-09-13 | PXD028151 | Pride
Project description:Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-drivencellular change.
2024-04-09 | GSE261297 | GEO
Project description:The Golgi apparatus plays a central role in the protein glycosylation where it is required for secretory trafficking. Abnormal morphology of the Golgi apparatus has been widely observed in neurodegenerative disease. Golgi pH regulator (GPHR) is an anion channel essential for acidification of the Golgi lumen and its essential for normal morphology and function of the Golgi apparatus. To address the Golgi dysfunction in neuronal cells, we established brain-specific GPHR knockout mice (GPHRf/f;Nes).
2022-08-31 | GSE208622 | GEO
Project description:Golgi resident proteins in Arabidopsis thaliana are challenging to quantify since the abundance of this organelle is relatively low within the cell. In this study an organelle fractionation approach, targeting the Golgi apparatus, was combined with a label free quantitative MS, data-independent acquisition (DIA) method employing ion mobility separation known as LC-IMS-MSE, to simultaneously localise proteins to the Golgi apparatus and assess their relative quantity. In total 33 proteins were localised to Golgi apparatus and 102 Golgi localised proteins were quantified.
2016-07-07 | PXD001056 | Pride