Academic literature on the topic 'Ca2+ lysosomal'
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Journal articles on the topic "Ca2+ lysosomal"
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Wang, Wuyang, Xiaoli Zhang, Qiong Gao, Maria Lawas, Lu Yu, Xiping Cheng, Mingxue Gu, et al. "A voltage-dependent K+ channel in the lysosome is required for refilling lysosomal Ca2+ stores." Journal of Cell Biology 216, no. 6 (May 3, 2017): 1715–30. http://dx.doi.org/10.1083/jcb.201612123.
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The resting membrane potential (Δψ) of the cell is negative on the cytosolic side and determined primarily by the plasma membrane’s selective permeability to K+. We show that lysosomal Δψ is set by lysosomal membrane permeabilities to Na+ and H+, but not K+, and is positive on the cytosolic side. An increase in juxta-lysosomal Ca2+ rapidly reversed lysosomal Δψ by activating a large voltage-dependent and K+-selective conductance (LysoKVCa). LysoKVCa is encoded molecularly by SLO1 proteins known for forming plasma membrane BK channels. Opening of single LysoKVCa channels is sufficient to cause the rapid, striking changes in lysosomal Δψ. Lysosomal Ca2+ stores may be refilled from endoplasmic reticulum (ER) Ca2+ via ER–lysosome membrane contact sites. We propose that LysoKVCa serves as the perilysosomal Ca2+ effector to prime lysosomes for the refilling process. Consistently, genetic ablation or pharmacological inhibition of LysoKVCa, or abolition of its Ca2+ sensitivity, blocks refilling and maintenance of lysosomal Ca2+ stores, resulting in lysosomal cholesterol accumulation and a lysosome storage phenotype.
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Rodríguez, Ana, Paul Webster, Javier Ortego, and Norma W. Andrews. "Lysosomes Behave as Ca2+-regulated Exocytic Vesicles in Fibroblasts and Epithelial Cells." Journal of Cell Biology 137, no. 1 (April 7, 1997): 93–104. http://dx.doi.org/10.1083/jcb.137.1.93.
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Lysosomes are considered to be a terminal degradative compartment of the endocytic pathway, into which transport is mostly unidirectional. However, specialized secretory vesicles regulated by Ca2+, such as neutrophil azurophil granules, mast cell–specific granules, and cytotoxic lymphocyte lytic granules, share characteristics with lysosomes that may reflect a common biogenesis. In addition, the involvement of Ca2+ transients in the invasion mechanism of the parasite Trypanosoma cruzi, which occurs by fusion of lysosomes with the plasma membrane, suggested that lysosome exocytosis might be a generalized process present in most cell types. Here we demonstrate that elevation in the intracellular free Ca2+ concentration of normal rat kidney (NRK) fibroblasts induces fusion of lysosomes with the plasma membrane. This was verified by measuring the release of the lysosomal enzyme β-hexosaminidase, the appearance on the plasma membrane of the lysosomal glycoprotein lgp120, the release of fluid-phase tracers previously loaded into lysosomes, and the release of the lysosomally processed form of cathepsin D. Exposure to the Ca2+ ionophore ionomycin or addition of Ca2+containing buffers to streptolysin O–permeabilized cells induced exocytosis of ∼10% of the total lysosomes of NRK cells. The process was also detected in other cell types such as epithelial cells and myoblasts. Lysosomal exocytosis was found to require micromolar levels of Ca2+ and to be temperature and ATP dependent, similar to Ca2+-regulated secretory mechanisms in specialized cells. These findings highlight a novel role for lysosomes in cellular membrane traffic and suggest that fusion of lysosomes with the plasma membrane may be an ubiquitous form of Ca2+-regulated exocytosis.
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Xu, Ming, Xiaoxue Li, Scott W. Walsh, Yang Zhang, Justine M. Abais, Krishna M. Boini, and Pin-Lan Li. "Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes." American Journal of Physiology-Cell Physiology 304, no. 5 (March 1, 2013): C458—C466. http://dx.doi.org/10.1152/ajpcell.00342.2012.
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Activation of the death receptor Fas has been reported to produce a two-phase intracellular Ca2+ release response in coronary arterial myocytes (CAMs), which consists of local Ca2+ bursts via lysosomal transient potential receptor-mucolipin 1 (TRP-ML1) channels and consequent Ca2+ release from the sarcoplasmic reticulum (SR). The present study was designed to explore the molecular mechanism by which lysosomal Ca2+ bursts are coupled with SR Ca2+ release in mouse CAMs and to determine the functional relevance of this lysosome-associated two-phase Ca2+ release to apoptosis, a common action of Fas activation with Fas ligand (FasL). By confocal microscopy, we found that transfection of CAMs with TRP-ML1 small interfering (si)RNA substantially inhibited FasL (10 ng/ml)-induced lysosome Ca2+ bursts and consequent SR Ca2+ release. In contrast, transfection of CAMs with plasmids containing a full-length TRP-ML1 gene enhanced FasL-induced two-phase Ca2+ release. We further demonstrated that FasL significantly increased the colocalization of the lysosomal marker Lamp1 with ryanodine receptor 3 and enhanced a dynamic trafficking of lysosomes to the SR. When CAMs were treated with TRP-ML1 siRNA, FasL-induced interactions between the lysosomes and SR were substantially blocked. Functionally, FasL-induced apoptosis and activation of calpain and calcineurin, the Ca2+ sensitive proteins that mediate apoptosis, were significantly attenuated by silencing TRP-ML1 gene but enhanced by overexpression of TRP-ML1 gene. These results suggest that TRP-ML1 channel-mediated lysosomal Ca2+ bursts upon FasL stimulation promote lysosome trafficking and interactions with the SR, leading to apoptosis of CAMs via a Ca2+-dependent mechanism.
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Peng, Wesley, Yvette C. Wong, and Dimitri Krainc. "Mitochondria-lysosome contacts regulate mitochondrial Ca2+dynamics via lysosomal TRPML1." Proceedings of the National Academy of Sciences 117, no. 32 (July 23, 2020): 19266–75. http://dx.doi.org/10.1073/pnas.2003236117.
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Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria–lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria–lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria–lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria–lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
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Burlando, Bruno, Barbara Marchi, Isabella Panfoli, and Aldo Viarengo. "Essential role of Ca2+-dependent phospholipase A2in estradiol-induced lysosome activation." American Journal of Physiology-Cell Physiology 283, no. 5 (November 1, 2002): C1461—C1468. http://dx.doi.org/10.1152/ajpcell.00429.2001.
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The mechanism of lysosome activation by 17β-estradiol has been studied in mussel blood cells. Cell treatment with estradiol induced a sustained increase of cytosolic free Ca2+that was completely prevented by preincubating the cells with the Ca2+chelator BAPTA-AM. Estradiol treatment was also followed by destabilization of the lysosomal membranes, as detected in terms of the lysosomes' increased permeability to neutral red. The effect of estradiol on lysosomes was almost completely prevented by preincubation with the inhibitor of cytosolic Ca2+-dependent PLA2(cPLA2), arachidonyl trifluoromethyl ketone (AACOCF3), and was significantly reduced by preincubation with BAPTA-AM. In contrast, it was virtually unaffected by preincubation with the inhibitor of Ca2+-independent PLA2, ( E)-6-(bromomethylene)tetrahydro-3-(1-naphtalenyl)-2 H-pyran-2-one (BEL). The Ca2+ionophore A-23187 yielded similar effects on [Ca2+]iand lysosomes. Exposure to estradiol also resulted in cPLA2translocation from cytosol to membranes, lysosome enlargement, and increased protein degradation. These results suggest that the destabilization of lysosomal membranes following cell exposure to estradiol occurs mainly through a Ca2+-dependent mechanism involving activation of Ca2+-dependent PLA2. This mechanism promotes lysosome fusion and catabolic activities and may mediate short-term estradiol effects.
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Li, Guangbi, Dandan Huang, Jinni Hong, Owais M. Bhat, Xinxu Yuan, and Pin-Lan Li. "Control of lysosomal TRPML1 channel activity and exosome release by acid ceramidase in mouse podocytes." American Journal of Physiology-Cell Physiology 317, no. 3 (September 1, 2019): C481—C491. http://dx.doi.org/10.1152/ajpcell.00150.2019.
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The transient receptor potential mucolipin 1 (TRPML1) channel has been reported to mediate lysosomal Ca2+ release that is involved in Ca2+-dependent lysosome trafficking and autophagic flux. However, this regulatory mechanism of lysosomal TRPML1 channel activity in podocytes remains poorly understood. In the present study, we tested whether the TRPML1 channel in podocytes mediates lysosome trafficking, which is essential for multivesicular body (MVB) degradation by lysosomes. We first demonstrated the abundant expression of TRPML1 channel in podocytes. By GCaMP3 Ca2+ imaging, we characterized the lysosomal specificity of TRPML1 channel-mediated Ca2+ release in podocytes. Given the important role of acid ceramidase (AC) in lysosome function and podocyte injury, we tested whether AC regulates this TRPML1 channel-mediated Ca2+ release and consequent lysosome-dependent MVB degradation in podocytes. Pharmacologically, it was found that TRPML1 channel activity was remarkably attenuated by the AC inhibitor carmofur. Sphingosine, as an AC product, was demonstrated to induce TRPML1-mediated Ca2+ release, which was inhibited by a TRPML1 blocker, verapamil. Using a Port-a-Patch planar patch-clamp system, we found that AC-associated sphingolipids, sphingomyelin, ceramide, and sphingosine had different effects on TRPML1 channel activity in podocytes. Functionally, the inhibition of AC or blockade of TRPML1 channels was found to suppress the interaction of lysosomes and MVBs, leading to increased exosome release from podocytes. These results suggest that AC is critical for TRPML1 channel-mediated Ca2+ release, which controls lysosome-MVB interaction and exosome release in podocytes.
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McCue, Hannah V., Joanna D. Wardyn, Robert D. Burgoyne, and Lee P. Haynes. "Generation and characterization of a lysosomally targeted, genetically encoded Ca2+-sensor." Biochemical Journal 449, no. 2 (December 14, 2012): 449–57. http://dx.doi.org/10.1042/bj20120898.
Full textAbstract:
Distinct spatiotemporal Ca2+ signalling events regulate fundamental aspects of eukaryotic cell physiology. Complex Ca2+ signals can be driven by release of Ca2+ from intracellular organelles that sequester Ca2+ such as the ER (endoplasmic reticulum) or through the opening of Ca2+-permeable channels in the plasma membrane and influx of extracellular Ca2+. Late endocytic pathway compartments including late-endosomes and lysosomes have recently been observed to sequester Ca2+ to levels comparable with those found within the ER lumen. These organelles harbour ligand-gated Ca2+-release channels and evidence indicates that they can operate as Ca2+-signalling platforms. Lysosomes sequester Ca2+ to a greater extent than any other endocytic compartment, and signalling from this organelle has been postulated to provide ‘trigger’ release events that can subsequently elicit more extensive Ca2+ signals from stores including the ER. In order to investigate lysosomal-specific Ca2+ signalling a simple method for measuring lysosomal Ca2+ release is essential. In the present study we describe the generation and characterization of a genetically encoded, lysosomally targeted, cameleon sensor which is capable of registering specific Ca2+ release in response to extracellular agonists and intracellular second messengers. This probe represents a novel tool that will permit detailed investigations examining the impact of lysosomal Ca2+ handling on cellular physiology.
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Rao, Swathi K., Chau Huynh, Veronique Proux-Gillardeaux, Thierry Galli, and Norma W. Andrews. "Identification of SNAREs Involved in Synaptotagmin VII-regulated Lysosomal Exocytosis." Journal of Biological Chemistry 279, no. 19 (March 1, 2004): 20471–79. http://dx.doi.org/10.1074/jbc.m400798200.
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Ca2+-regulated exocytosis of lysosomes has been recognized recently as a ubiquitous process, important for the repair of plasma membrane wounds. Lysosomal exocytosis is regulated by synaptotagmin VII, a member of the synaptotagmin family of Ca2+-binding proteins localized on lysosomes. Here we show that Ca2+-dependent interaction of the synaptotagmin VII C2A domain with SNAP-23 is facilitated by syntaxin 4. Specific interactions also occurred in cell lysates between the plasma membrane t-SNAREs SNAP-23 and syntaxin 4 and the lysosomal v-SNARE TI-VAMP/VAMP7. Following cytosolic Ca2+elevation, SDS-resistant complexes containing SNAP-23, syntaxin 4, and TI-VAMP/VAMP7 were detected on membrane fractions. Lysosomal exocytosis was inhibited by the SNARE domains of syntaxin 4 and TI-VAMP/VAMP7 and by cleavage of SNAP-23 with botulinum neurotoxin E, thereby functionally implicating these SNAREs in Ca2+-regulated exocytosis of conventional lysosomes.
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Bakker, A. C., P. Webster, W. A. Jacob, and N. W. Andrews. "Homotypic fusion between aggregated lysosomes triggered by elevated [Ca2+]i in fibroblasts." Journal of Cell Science 110, no. 18 (September 15, 1997): 2227–38. http://dx.doi.org/10.1242/jcs.110.18.2227.
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Previous studies demonstrated that microinjection of antibodies to the cytoplasmic domain of the lysosomal glycoprotein lgp120 induces aggregation of lysosomes in NRK cells. Here we show that the antibody-clustered vesicles do not co-localize with MPR and ss-COP-containing organelles, confirming their lysosomal nature. Observations by transmission and high voltage electron microscopy indicated that, although tightly apposed to each other, aggregated lysosomes remained as separate vesicles, with an average diameter of 0.3-0.4 micron. However, when cells microinjected with antibody were exposed to the Ca2+ ionophore ionomycin, large vesicles were formed within the lysosome clusters, suggesting the occurrence of lysosome-lysosome fusion. Stereological measurements of lysosome diameters on confocal and transmission electron microscopy indicated that the large lgp120-positive vesicles could have originated from the fusion of 3 up to 15 individual lysosomes. To verify if agents that mobilize Ca2+ from intracellular stores had the same effect, anti-lgp120-microinjected cells were treated with thapsigargin, and with the receptor-mediated agonists bombesin and thrombin. Thapsigargin also induced the formation of large lgp120-containing vesicles, detected by both confocal and transmission electron microscopy. Analysis of antibody-clustered lysosomes in streptolysin O-permeabilized cells indicated that an intracellular free Ca2+ concentration of 1 microM was sufficient to trigger formation of large lysosomes.
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Flannery, Andrew R., Cecilia Czibener, and Norma W. Andrews. "Palmitoylation-dependent association with CD63 targets the Ca2+ sensor synaptotagmin VII to lysosomes." Journal of Cell Biology 191, no. 3 (November 1, 2010): 599–613. http://dx.doi.org/10.1083/jcb.201003021.
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Syt VII is a Ca2+ sensor that regulates lysosome exocytosis and plasma membrane repair. Because it lacks motifs that mediate lysosomal targeting, it is unclear how Syt VII traffics to these organelles. In this paper, we show that mutations or inhibitors that abolish palmitoylation disrupt Syt VII targeting to lysosomes, causing its retention in the Golgi complex. In macrophages, Syt VII is translocated simultaneously with the lysosomal tetraspanin CD63 from tubular lysosomes to nascent phagosomes in a Ca2+-dependent process that facilitates particle uptake. Mutations in Syt VII palmitoylation sites block trafficking of Syt VII, but not CD63, to lysosomes and phagosomes, whereas tyrosine replacement in the lysosomal targeting motif of CD63 causes both proteins to accumulate on the plasma membrane. Complexes of CD63 and Syt VII are detected only when Syt VII palmitoylation sites are intact. These findings identify palmitoylation-dependent association with the tetraspanin CD63 as the mechanism by which Syt VII is targeted to lysosomes.
Dissertations / Theses on the topic "Ca2+ lysosomal"
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Ghislat, Cherfaoui Ghita. "Regulation of Lysosomal Degradation by CA2+And CA2+-Binding Proteins." Doctoral thesis, Universitat Politècnica de València, 2013. http://hdl.handle.net/10251/29690.
Full textAbstract:
La macroautofagia y la endocitosis son dos procesos catabólicos
conservados evolutivamente en los que, mediante un tráfico vesicular, se
degrada el material secuestrado, cuyo origen es intra- y extracelular,
respectivamente. Ambos procesos comienzan de manera diferente:
mediante la formación de un nuevo orgánulo, el autofagosoma, que
secuestra material citoplásmico (macroautofagia), o mediante la
internalización de material extracelular y de algunos componentes de la
membrana plasmática a través de vesículas endocíticas (endocitosis). Sin
embargo, los dos terminan en el mismo compartimiento: el lisosoma.
En un análisis proteómico de membranas lisosomales, purificadas a
partir de fibroblastos de ratón, identificamos tres proteínas, que se unen a
fosfolípidos de una manera dependiente de calcio, y cuyos niveles en la
membrana lisosomal aumentaban en ausencia de aminoácidos, una
condición que activa la macroautofagia. Basándonos en esos resultados
iniciales, y teniendo en cuenta que el calcio es un segundo mensajero muy
importante, decidimos: en primer lugar, abordar el papel del calcio en la
activación de la autofagia producida por el ayuno de aminoácidos, y, en
segundo lugar, investigar el papel de esas tres proteínas en el mecanismo
autofágico.
Como resultado de estos estudios, describimos en primer lugar una
nueva vía de señalización dependiente de calcio que activa la formación de
autofagosomas por los aminoácidos. Concretamente, hemos encontrado
que el ayuno de aminoácidos esenciales produce un aumento en el calcio
citosólico, procedente tanto del medio extracelular como de almacenes
intracelulares. Como consecuencia de esto, la calmodulina quinasa quinasa-
ß activa a AMPK y a mTORC1. En la última etapa de esta vía, ULK1, una
quinasa responsable de la iniciación de la autofagia, se activa para
contribuir a la formación de los autofagosomas.
Las tres proteínas identificadas en el estudio proteómico y cuyos
niveles en las membranas lisosomales aumentan en ausencia de aminoácidos son la anexina A1, la anexina A5 y la copina 1. Empleando
métodos bioquímicos y de inmunofluorescencia observamos que el ayuno
de aminoácidos causa la translocación de la anexina A5 desde el complejo
de Golgi hasta las membranas lisosomales, donde también se acumulan la
anexina A1 y la copina 1. Asimismo, demostramos por sobre-expresión y
silenciamiento de esas tres proteínas, que las tres inducen la fusión de
autofagosomas con lisosomas y que la copina 1, y en menor medida la
anexina A1, aumentan el efecto individual de la anexina A5. Finalmente, la
anexina A5 inhibe la endocitosis mientras que copina 1 la induce.
En resumen, nuestros resultados ponen de manifiesto que la
activación de la formación de autofagosomas por el ayuno de aminoácidos
es debida, al menos en parte, a una vía de señalización dependiente de
Ca2+
y que esta condición también conlleva la aceleración de la maduración
de los autofagosomas a autolisosomas a través de proteínas que unen el
Ca2+ como las anexinas A1 y A5 y la copina 1.Ghislat Cherfaoui, G. (2013). Regulation of Lysosomal Degradation by CA2+And CA2+-Binding Proteins [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/29690
TESIS
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Yates, Elizabeth Lucy. "Lysosomal Ca2+ signalling and neurodegeneration : a global view." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10038577/.
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Dysfunction of the lysosomal Ca2+ channels TRPML1 and TPC2 has been implicated in neurodegenerative disease. However, there is little information about the involvement of these channels in cell-wide global Ca2+ signalling and it is unknown whether their dysfunction contributes to neurodegeneration by disturbing it. First, by using synthetic compounds, I demonstrate that TRPML1 activation causes global Ca2+ signals. In contrast with the predominant lysosomal localisation of the channel these Ca2+ signals comprised a small lysosomal contribution and a large Ca2+ entry component. Examination of TRPML1-mediated Fe2+ entry posed the possibility that divalent cation entry can occur directly through TRPML1 on the plasma membrane. Second, I identified enlarged and clustered lysosomes in fibroblasts derived from people with sporadic Parkinson’s disease (PD). This was appropriately quantified from microscopy images by creating an automated sequence of image processing functions. By inhibiting TPC expression in fibroblasts I demonstrated their involvement in the propagation of physiological global Ca2+ signals evoked by bradykinin. In sporadic and familial PD patient fibroblasts these TPCdependent Ca2+ signals were subtly modulated. Finally, in a neuronal cell line, reduced TPC expression inhibited the propagation of physiological global Ca2+ signals evoked by carbachol. These Ca2+ signals were also blocked by a recently identified TPC blocker and by putative TPC blockers that were screened by collaborators. In cells expressing the PD-associated mutant, LRRK2 G2019S, these TPC-dependent Ca2+ signals were potentiated. In contrast, bradykinin-evoked Ca2+ signals in this neuronal cell line were not inhibited by TPC blockers, nor were they potentiated in the LRRK2 G2019S cells. Therefore, physiological global Ca2+ signalling in PD may be perturbed by TPC dysfunction, and be a compounding factor in neurodegeneration. Collectively this research suggests that lysosomal Ca2+ signalling through TRPML1 and TPCs plays a role in global Ca2+ signalling and that this may be disturbed in neurodegenerative disease.
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Serrano, Daniel. "GIMAP5 influence la survie des cellules T naïves en participant à la régulation du calcium emmagasiné dans les organites." Thèse, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/11088.
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La survie des cellules T naïves est essentielle au bon fonctionnement du système immunitaire à long terme. Les rats BBDP (Bio-breeding Diabetes prone) sont caractérisés par une haute prédisposition au développement du diabète ainsi que par une diminution significative du nombre de cellules T naïves. Ces rats comportent une mutation de type décalage de lecture dans le gène codant pour «GTPase Immunity-Associated Protein 5» (Gimap5) ce qui entraine l’apoptose des lymphocytes T. Le mécanisme par lequel la déficience de la protéine GIMAP5 conduit les cellules T à la mort est actuellement méconnu. GIMAP5 a également été associée à différentes maladies auto-immunes, ce qui suggère son influence dans l'homéostasie des lymphocytes T. Des résultats antérieurs de notre groupe de recherche ont montré que l'absence de GIMAP5 entraîne une diminution du flux de Ca2+ ainsi qu’une réduction de la capacité mitochondriale à emmagasiner du Ca2+ suite à la stimulation du TCR. Cependant, GIMAP5 n'est pas une protéine mitochondriale. Afin de mieux comprendre le rôle de GIMAP5 dans la biologie des cellules T, au cours de mes études doctorales, je me suis concentré sur la localisation cellulaire de la protéine ainsi que sur son rôle dans l'homéostasie du Ca2+. Comme modèle d’étude, j'ai établi des lignées cellulaires HEK293T stables pour l’expression de GIMAP5, ainsi que pour différents mutants et variantes de la protéine. Ceci m’a permis d’élucider l'importance du domaine transmembranaire (TM) pour la localisation et le rôle physiologique de GIMAP5 ainsi que la différence entre les deux variantes de cette protéine.
Mes résultats ont permis de montrer que l'expression de Gimap5 ne semble pas être nécessaire après l’activation des lymphocytes T. En parallèle, j'ai confirmé nos observations antérieures qui démontrent l’influence de GIMAP5 dans l'homéostasie du Ca2+ et sa colocalization avec les microtubules. En outre, j'ai montré que GIMAP5 se trouve dans des structures de type vésiculaire, particulièrement dans la membrane lysosomale où son domaine TM est essentiel à son bon fonctionnement et localisation. Mes résultats suggèrent que les mitochondries exhibent un défaut dans leur capacité à emmagasiner du Ca2+ au niveau basal, ainsi que suite à l’activation du TCR. Enfin, j'ai démontré pour la première fois, que l'influence de GIMAP5 sur le stockage de Ca2+ lysosomal peut avoir un impact sur la survie des lymphocytes T. D’après ces observations, une des fonctions probables de GIMAP5 serait d’empêcher la fermeture prématurée des canaux de relâche calcique. Finalement, GIMAP5 pourrait être engagé dans des mécanismes visant à prolonger et raffiner la signalisation du Ca2+ dans les cellules T. Bref, la régulation du Ca2+ lysosomal médié par GIMAP5 est essentielle à la survie de cellules T naïves.Abstract: Healthy and long-term survival of naïve T cells is essential for proper functioning of the immune system. In bio-breeding diabetes prone (BBDP) rats, there is a critical decrease in the number of naïve T cells. In these rats, a recessive frameshift mutation in the GTPase of Immune-Associated Protein 5 (Gimap5) gene induces lymphocytes to undergo spontaneous apoptosis. The death of T cells driven by a deficiency of the GIMAP5 is currently not fully understood. Interestingly, different autoimmune diseases have shown an association with perturbations in the Gimap5 gene, which further suggests its influence in basal lymphocyte homeostasis. Previous findings by our group have shown that the absence of GIMAP5 results in a decrease calcium flux following TCR stimulation and an impaired capacity of the mitochondria to buffer calcium entry. However, GIMAP5 is not a mitochondrial protein. During my Ph.D. studies, I focused on clarifying the cellular localization of GIMAP5 as well as its function in Ca2+ homeostasis in order to further understand its role in T cell biology. As a model, I established HEK293T cells stable for the expression of the different mutants and variants of the GIMAP5 protein. Where I uncovered the importance of the transmembrane domain (TM) for GIMAP5 localization and physiological role, as well as the differences between the two variants of GIMAP5. The results obtained show that the expression of Gimap5 is no longer needed after T cells activation. Moreover, our previous observations were confirmed and expanded upon regarding GIMAP5’s influence on Ca2+ homeostasis and colocalization with the cytoskeleton. It was also shown that GIMAP5 localizes to vesicular-like structures, particularly to the lysosomal membrane, where its TM domain is critical for proper functioning and localization. My results suggest that the mitochondria might be impaired to uptake as well as retain Ca2+ at their full capacity in the absence of GIMAP5. Finally, I observed for the first time that GIMAP5’s influence on lysosomal Ca2+ storage could impact lymphocyte survival. These results suggest that GIMAP5 may work as a backup mechanism to prevent premature closure of Ca2+ channels and Ca2+ influx or as a mechanism to prolong and refine Ca2+ signaling in T cells.
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Foster, Willam. "The effects of lysosomal Ca2+ release on membrane depolarisation and synaptic plasticity in hippocampus." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:044cb37b-fdb7-4c19-b6f7-c9e261817751.
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Intracellular Ca2+ signalling is essential for the control of almost every physiological process, from muscular contraction to synaptic transmission. Intracellular Ca2+ signals can be generated from both extracellular or intracellular Ca2+ stores. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous and important Ca2+ mobilising second messenger. NAADP signalling causes Ca2+ release from intracellular acidic Ca2+ stores. The functional roles of NAADP signalling and acidic store Ca2+ release in the central nervous system are relatively unknown Brailoiu et al. (2009b) showed that NAADP signalling enhances membrane excitability in neurons of the medulla, Padamsey and Emptage (2011) (Unpublished) find similar effects in pyramidal neurons of the hippocampus. I used pharmacological manipulations in combination with electrophysiological techniques and dendritic Ca2+ imaging to explore the effect of NAADP/acidic store signalling on membrane excitability and synaptic plasticity in pyramidal neurons of the hippocampus. I began by using a membrane permeable form of NAADP (NAADP-AM) to show NAADP/acidic store Ca2+ signalling caused membrane depolarisation. I also showed, with intracellular dialysis of Ca2+ mobilising second messengers, NAADP is unique in its ability to directly cause membrane depolarisation. I then identified glutamate, acting via metabotropic glutamate receptor 1 (mGluR1), as an endogenous stimulus that causes NAADP-mediated Ca2+ release and depolarisation. I next elucidated the signalling pathway responsible for mGluR1/NAADP-mediated depolarisation and showed the requirement of acidic store Ca2+ release, and subsequent amplification of this Ca2+ via ryanodine receptors by Ca2+-induced Ca2+ release. The resulting Ca2+ signal caused inhibition of small conductance K+ channels (SK channels) and membrane depolarisation. SK channels are described to facilitate the induction of plasticity in hippocampal synapses by modulation of GluN Ca2+ entry (Ngo-Anh et al., 2005). Finally, I show that the induction of mGluR1-dependent long-term potentiation requires inhibition of the SK channels via NAADP/acidic store Ca2+ signalling. Group 1 mGluRs are implicated in the pathogenesis of neurodevelopmental disorders such as fragile X syndrome. My findings may identify new targets for the treatment of such diseases.
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Atakpa, Peace. "Ca2+ signalling between the endoplasmic reticulum and lysosomes." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288002.
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Ca2+ is a universal and versatile intracellular messenger, regulating a vast array of biological processes due to variations in the frequency, amplitude, spatial and temporal dynamics of Ca2+ signals. Increases in cytosolic free Ca2+ concentration ([Ca2+]c) are due to influx from either an infinite extracellular Ca2+ pool or from the more limited intracellular Ca2+ stores. Stimulation of the endogenous muscarinic (M3) receptors of human embryonic kidney (HEK) cells with carbachol results in the activation of phospholipase C (PLC) and formation of inositol 1,4,5-trisphosphate (IP3), activation of IP3 receptors (IP3Rs), release of Ca2+ from the endoplasmic reticulum (ER), and activation of store-operated Ca2+ entry (SOCE). Lysosomes are the core digestive compartments of the cell, but their importance as signalling organelles is also now widely appreciated. Accumulating evidence indicates that lysosomal Ca2+ is important for their physiological functions. Lysosomal Ca2+ release triggers fusion during membrane trafficking and, through calmodulin, it regulates lysosome size. Luminal Ca2+ is critical for regulation of lysosomal biogenesis and autophagy during starvation through the transcription factor, TFEB. Furthermore, aberrant lysosomal Ca2+ is associated with some lysosomal storage diseases. Lysosomes in mammalian cells have long been suggested to accumulate Ca2+ via a low-affinity Ca2+-H+ exchanger (CAX). This is consistent with evidence that dissipating the lysosomal H+ gradient increased [Ca2+]c and decreased lysosomal free [Ca2+], and with the observation that lysosomal Ca2+ uptake was followed by an increase in pHly. Furthermore, heterologous expression of Xenopus CAX in mammalian cells attenuated carbachol-evoked Ca2+ signals. However, there is no known CAX in mammalian cells, and so the identity of the lysosomal Ca2+ uptake pathway in mammalian cells is unresolved. Using mammalian cells loaded with a fluorescent Ca2+ indicator, I show that dissipating the pHly gradient pharmacologically or by siRNA-mediated knockdown of an essential subunit of the H+ pump, increases the amplitude of IP3-evoked cytosolic Ca2+ signals without affecting those evoked by SOCE. A genetically encoded low-affinity Ca2+ sensor expressed on the lysosome surface reports larger increases in [Ca2+]c than the cytosolic sensor, but only when the Ca2+ signals are evoked by IP3R rather than SOCE. Using cells expressing single IP3R subtypes, I demonstrate that each of the three IP3R subtypes can deliver Ca2+ to lysosomes. I conclude that IP3Rs release Ca2+ within near-lysosome microdomains that fuel a low-affinity lysosomal Ca2+ uptake system. The temporal relationship between the increase in pHly and reduced Ca2+ sequestration suggests that pHly affects the organization of the microdomain rather than the Ca2+ uptake mechanism. I show that abrogation of the lysosome H+ gradient does not acutely prevent uptake of Ca2+ into lysosomes, but disrupts junctions with the ER where the exchange of Ca2+ occurs. The dipeptide, glycyl-L-phenylalanine 2-naphthylamide (L-GPN), is much used to disrupt lysosomes and release Ca2+ from them. The mechanism is widely assumed to require cleavage of GPN by cathepsin C, causing accumulation of amino acid residues, and osmotic lysis of lysosomal membranes. I show, using LysoTracker Red and Oregon Green-dextran to report pHly, that L-GPN is effective in HEK cells lacking functional cathepsin C, following CRISPR-Cas9-mediated gene disruption. Furthermore, D-GPN, which is resistant to cleavage by cathepsin C, is as effective as L-GPN at increasing pHly, and it is similarly effective in cells with and without cathepsin C. L-GPN and D-GPN increase cytosolic pH, and the effect is similar when the lysosomal V-ATPase is inhibited with bafilomycin A1. This is not consistent with GPN releasing the acidic contents of lysosomes. I conclude that the effects of GPN on lysosomes are not mediated by cathepsin C. Both L-GPN and D-GPN evoke Ca2+ release, the response is unaffected by inhibition or knock-out of cathepsin C, but it requires Ca2+ within the ER. GPN-evoked increases in [Ca2+]c require Ca2+ within the ER, but they are not mediated by ER Ca2+ channels amplifying Ca2+ release from lysosomes. GPN increases [Ca2+]c by increasing pHcyt, which then directly stimulates Ca2+ release from the ER. I conclude that physiologically relevant increases in pHcyt stimulate Ca2+ release from the ER independent of IP3 and ryanodine receptors, and that GPN does not selectively target lysosomes. I conclude that all three IP3R subtypes selectively deliver Ca2+ to lysosomes, and that the low pH within lysosomes is required to maintain the junctions between ER and lysosomes, but not for lysosomal Ca2+ uptake. I suggest that GPN lacks the specificity required to allow selective release of Ca2+ from lysosomes.
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Rockwell, Hannah. "AAV-Mediated Gene Delivery Corrects CNS Lysosomal Storage in Cats with Juvenile Sandhoff Disease." Thesis, Boston College, 2013. http://hdl.handle.net/2345/3929.
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Thesis advisor: Thomas N. SeyfriedSandhoff Disease (SD) is an autosomal recessive neurodegenerative disease caused by a mutation in the Hexb gene for the β-subunit of β-hexosaminidase A, resulting in the inability to catabolize ganglioside GM2 within the lysosomes. SD presents with an accumulation of GM2 and its asialo derivative GA2 primarily in the CNS. Myelin-enriched glycolipids, cerebrosides and sulfatides, are also decreased in SD corresponding with dysmyelination. At present, no treatment exists for SD. Previous studies have shown the therapeutic benefit of using adeno-associated virus (AAV) vector-mediated gene therapy in the treatment of SD in murine and feline models. In this study, CNS tissue was evaluated from SD cats (4-6 week old) treated with bilateral injections of AAVrh8 expressing feline β-hexosaminidase α and β into the thalamus and deep cerebellar nuclei (Thal/DCN) or into the thalamus combined with intracerebroventricular injections (Thal/ICV). Both groups of treated animals had previously shown improved quality of life and absence of whole-body tremors. The activity of β-hexosaminidase was significantly elevated whereas the content of GM2 and GA2 was significantly decreased in tissue samples taken from the cerebral cortex, cerebellum, thalamus, and cervical intumescence. Treatment also increased levels of myelin-enriched cerebrosides and sulfatides in the cortex and thalamus. This study demonstrates the therapeutic benefits of AAV treatment for feline SD and suggests a similar potential for human SD patients
Thesis (MS) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
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Das, Ghatak Piya. "Inhibition of TFEB activation promotes Coxiella burnetii growth." Thesis, 2021. http://dx.doi.org/10.7912/C2/23.
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Indiana University-Purdue University Indianapolis (IUPUI)Coxiella burnetii is the etiologic agent of Q fever, a zoonotic disease characterized by flu-like sickness in acute cases; endocarditis may occur and turn deadly if not treated correctly in chronic patients. Coxiella, an obligate intracellular bacterium, requires establishment of a replicative niche in the host cell. After being phagocytosed by the eukaryotic cell, the bacterium resides in a tight-fitting nascent phagosome which matures through the host canonical endocytic pathway, acquiring endosomal/lysosomal markers as well as acidic pH. Initial acidification of the Coxiella containing vacuole (CCV) is central to the bacterium’s pathogenesis because translocation of bacterial effector proteins into the host cell by the type 4B secretion system (T4BSS) initiates only after it senses the acidic environment. The effector proteins are required for subverting different host cell functions in favor of Coxiella growth, CCV maturation and are crucial for bacterial virulence. Contrary to the belief that since CCV matures through the host endocytic pathway, CCV is as acidic as lysosome, we found that CCV is significantly less acidic (pH~5.2) than lysosomes (pH~4.8) and inducing further CCV acidification causes Coxiella lysis. Furthermore, increasing lysosomal biogenesis in the host cell is detrimental for Coxiella growth. So, we hypothesized that Coxiella blocks lysosomal biogenesis in host cells to maintain the CCV pH just optimal for its growth. Lysosomal biogenesis is regulated by the master transcription factor EB (TFEB). Its ability to act as a transcription factor depends on its subcellular localization, which relies on its phosphorylation state. TFEB, when phosphorylated is cytosolic and inactive, whereas dephosphorylated TFEB translocates to the nucleus and is active, binding to promoter regions of lysosomal genes of the CLEAR network, thus controlling lysosome biogenesis. Therefore, we hypothesized that Coxiella blocks TFEB translocation to the nucleus, thus inhibiting lysosome biogenesis. We determined that Coxiella grows significantly better in TFEB-KO cells than they do in parentals. Also, using a torin-induced TFEB translocation model, we observed remarkably decreased TFEB activation in the Coxiella infected cells as was evident by less TFEB translocation to nucleus. Overall, data obtained from this work suggest that Coxiella inhibits lysosome biogenesis by blocking TFEB nuclear translocation.
Books on the topic "Ca2+ lysosomal"
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Poorthuis, Ben. Lysosomal Storage Disorders. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0046.
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Lysosomal storage disorders are characterized by the presence of nondegraded material in endosomal / lysosomal compartments. Any process that interferes with the lysosomal degradation or endosomal / lysosomal transport of molecules can give rise to storage. The cause may be genetic in nature or environmental, as is the case in drug-induced lipidoses or when undegradable materials are present. In this chapter we discuss the genetic lysosomal storage disorders.
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Waldek, Stephen. Fabry disease. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0335_update_001.
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Fabry disease is a rare X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the lysosomal acid hydrolase enzyme, alpha-galactosidase A. The resulting accumulation of substrate, mostly globotriaosylceramide, leads to a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, and nervous system. It is one of over 50 lysosomal storage diseases. It is typically diagnosed in young men after many years of ‘acral pain’ syndrome, when the diagnosis is made through identification of characteristic abnormalities of skin, kidney or heart, or of other organs. Renal failure has been a common outcome. Females may also develop manifestations, usually later in life. Renal biopsy shows vacuoles/deposits in podocytes and other renal cell types with progressive scarring. The diagnosis can be made by measuring enzyme levels in men, or by genetic testing. This latter is the more reliable test in women. Fabry disease can now be treated where affordable by regular (every 2 weeks) intravenous infusions of recombinant preparations of the deficient enzyme. These are burdensome and expensive, but are transforming the outlook for the condition.
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Cassiman, David, and Carla E. M. Hollak. Approach to the Patient with Hepato-Gastroenterological or Abdominal Signs and Symptoms. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0074.
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A variety of signs and symptoms related to the gastrointestinal tract, including the liver, can be found as a presenting symptom of an inborn error of metabolism in adults. In particular hepatomegaly, a frequent symptom of lysosomal storage disorders and hyperammonemia not caused by acquired liver disease are manifestations of a late presentation of a metabolic disorder. A wide variety of other symptoms and signs including jaundice, abdominal pain or diarrhea, may be caused by toxic metabolites or storage of undergraded macromolecules as well.
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Frawley, Geoff. Mucopolysaccharidoses. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199764495.003.0064.
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The mucopolysaccharidoses (MPS) are a group of seven chronic progressive diseases caused by deficiencies of 11 different lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). Hurler syndrome (MPS IH) is an autosomal recessive storage disorder caused by a deficiency of α-L-iduronidase. Hunter syndrome (MPS II) is an X-linked recessive disorder of metabolism involving the enzyme iduronate-2-sulfatase. Many of the MPS clinical manifestations have potential anesthetic implications. Significant airway issues are particularly common due to thickening of the soft tissues, enlarged tongue, short immobile neck, and limited mobility of the cervical spine and temporomandibular joints. Spinal deformities, hepatosplenomegaly, airway granulomatous tissue, and recurrent lung infections may inhibit pulmonary function. Odontoid dysplasia and radiographic subluxation of C1 on C2 is common and may cause anterior dislocation of the atlas and spinal cord compression.
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Waldek, Stephen. Fabry disease. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0337.
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Fabry disease is a rare X-linked lysosomal storage disorder in which deficiency of alpha-galactosidase A leads to accumulation of substrate, mostly globotriaosylceramide, which causes a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, and nervous system. Painful peripheral (‘acral’) neuropathy is characteristic.Key clinical signs are angiokeratoma found by close examination of skin; characteristic eye lesions may be seen; lipid deposits may be seen in urine. Renal biopsy appearances are characteristic and this is commonly where the diagnosis is first made. Increasingly, cardiologists are suspecting the condition in adults with echocardiographic appearances of left ventricular hypertrophy. Diagnosis in men is usually made by measurement of alpha-galactosidase in either white cells or plasma (or using blood spots). Unfortunately, many female patients can have normal enzyme levels so that genetic testing is the only way to confirm a diagnosis. Non-selective screening strategies (e.g. males on renal replacement therapy with uncertain renal diagnoses) have had low yields.
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Gaitanis, John, Phillip L. Pearl, and Howard Goodkin. The EEG in Degenerative Disorders of the Central Nervous System. Edited by Donald L. Schomer and Fernando H. Lopes da Silva. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190228484.003.0013.
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Nervous system alterations can occur at any stage of prenatal or postnatal development. Any of these derangements, whether environmental or genetic, will affect electrical transmission, causing electroencephalogram (EEG) alteration and possibly epilepsy. Genetic insults may be multisystemic (for example, neurocutaneous syndromes) or affect only the brain. Gene mutations account for inborn errors of metabolism, channelopathies, brain malformations, and impaired synaptogenesis. Inborn errors of metabolism cause seizures and EEG abnormalities through a variety of mechanisms, including disrupted energy metabolism (mitochondrial disorders, glucose transporter defect), neuronal toxicity (amino and organic acidopathies), impaired neuronal function (lysosomal and peroxisomal disorders), alteration of neurotransmitter systems (nonketotic hyperglycinemia), and vitamin and co-factor dependency (pyridoxine-dependent seizures). Environmental causes of perinatal brain injury often result in motor or intellectual impairment (cerebral palsy). Multiple proposed etiologies exist for autism, many focusing on synaptic development. This chapter reviews the EEG findings associated with this myriad of pathologies occurring in childhood.
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van der Ploeg, Ans T., and Pascal Laforêt. Pompe Disease. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0055.
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Pompe disease, also named acid maltase deficiency and glycogen storage disease type II (GSDII), is a rare autosomal recessive disorder caused by the deficiency of the glycogen-degrading lysosomal enzyme acid α-glucosidase. The clinical spectrum of this disease is broad, varying from a lethal infantile-onset generalized myopathy including cardiomyopathy, to late-onset slowly progressive muscle weakness mimicking limb-girdle muscular dystrophy. Respiratory insufficiency is a frequent complication and the main cause of death. The prognosis of Pompe disease has changed considerably with the use of enzyme replacement therapy using recombinant acid α-glucosidase (alglucosidase alfa), which has been widely available since 2006. Improvements in survival and major motor achievements can be observed in patients with infantile forms, and recent studies demonstrate improvement of walking distance and stabilization of pulmonary function in late-onset forms. A longer-term study of the safety and efficacy of ERT, based on data gathering across the complete spectrum of Pompe disease via national or international patient registries, is needed in order to formulate more precise guidelines for treatment.
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Goligorsky, Michael S., Julien Maizel, Radovan Vasko, May M. Rabadi, and Brian B. Ratliff. Pathophysiology of acute kidney injury. Edited by Norbert Lameire. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0221.
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In the intricate maze of proposed mechanisms, modifiers, modulators, and sensitizers for acute kidney injury (AKI) and diverse causes inducing it, this chapter focuses on several common and undisputable strands which do exist.Structurally, the loss of the brush border, desquamation of tubular epithelial cells, and obstruction of the tubular lumen are commonly observed, albeit to various degrees. These morphologic hallmarks of AKI are accompanied by functional defects, most consistently reflected in the decreased glomerular filtration rate and variable degree of reduction in renal blood flow, accompanied by changes in the microcirculation. Although all renal resident cells participate in AKI, the brunt falls on the epithelial and endothelial cells, the fact that underlies the development of tubular epithelial and vascular compromise.This chapter further summarizes the involvement of several cell organelles in AKI: mitochondrial involvement in perturbed energy metabolism, lysosomal involvement in degradation of misfolded proteins and damaged organelles, and peroxisomal involvement in the regulation of oxidative stress and metabolism, all of which become defective. Common molecular pathways are engaged in cellular stress response and their roles in cell death or survival. The diverse families of nephrotoxic medications and the respective mechanisms they induce AKI are discussed. The mechanisms of action of some nephrotoxins are analysed, and also of the preventive therapies of ischaemic or pharmacologic pre-conditioning.An emerging concept of the systemic inflammatory response triggered by AKI, which can potentially aggravate the local injury or tend to facilitate the repair of the kidney, is presented. Rational therapeutic strategies should be based on these well-established pathophysiological hallmarks of AKI.
Book chapters on the topic "Ca2+ lysosomal"
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Di Paola, Simone, and Diego L. Medina. "Ca2+-Dependent Regulation of TFEB and Lysosomal Function." In Calcium Signalling, 145–55. New York, NY: Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-9018-4_13.
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Edmond Wraith, J., and Michael Beck. "Clinical Aspects and Clinical Diagnosis." In Lysosomal Storage Disorders, 13–19. Oxford: John Wiley & Sons, Ltd, 2012. http://dx.doi.org/10.1002/9781118514672.ch2.
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Kirschke, H., J. Langner, S. Riemann, B. Wiederanders, S. Ansorge, and P. Bohley. "Lysosomal Cysteine Proteinases." In Ciba Foundation Symposium 75 - Protein Degradation in Health and Disease, 15–35. Chichester, UK: John Wiley & Sons, Ltd., 2008. http://dx.doi.org/10.1002/9780470720585.ch2.
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Reggiori, Fulvio, and Judith Klumperman. "Lysosome Biogenesis and Autophagy." In Lysosomes: Biology, Diseases, and Therapeutics, 7–31. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2016. http://dx.doi.org/10.1002/9781118978320.ch2.
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Attaix, Didier, and Daniel Taillandier. "The Critical Role of the Ubiquitin-Proteasome Pathway in Muscle Wasting in Comparison to Lysosomal and Ca2+-Dependent Systems." In Intracellular Protein Decradation, 235–66. Elsevier, 1998. http://dx.doi.org/10.1016/s1569-2558(08)60463-4.
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Fdil, Naima, Es-Said Sabir, Karima Lafhal, Noureddine Rada, Redouane El Fezzazi, Mohamed Amine, Fadl Mrahib Rabou Maoulainine, and Mohammed Bouskraoui. "Insights Into the COVID-19 Infection Related to Inherited Metabolic Diseases." In Handbook of Research on Pathophysiology and Strategies for the Management of COVID-19, 197–208. IGI Global, 2022. http://dx.doi.org/10.4018/978-1-7998-8225-1.ch012.
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People with respiratory problems and people prone to decompensations are particularly vulnerable to COVID-19. These characteristics are often present in patients with inherited metabolic diseases (IMDs). It is therefore conceivable that patients with IMDs are at a greater risk of infection and may present a more serious form of COVID-19 disease. Currently available data about the impact of COVID-19 on patients suffering from IMDs are very scarce and no study has been able to confirm this hypothesis. In this chapter, the authors have tried to show that the severity of COVID-19 infection in patients with IMDs is specific to the group that the disease belongs. Indeed, lysosomal storage diseases caused by impaired degradation and accumulation of metabolites in lysosomes leads to dysfunction of lysosomal and possible impairment of the COVID-19 egress process. The fact that COVID-19 disease may be considered itself as an IMD was also discussed to highlight the interference which can exist between COVID-19 disease and IMDs in a patient.
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Trauner, Doris A. "Neurological and Cognitive Consequences of Nephropathic Cystinosis." In Cognitive and Behavioral Abnormalities of Pediatric Diseases. Oxford University Press, 2010. http://dx.doi.org/10.1093/oso/9780195342680.003.0039.
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Nephropathic cystinosis is a rare autosomal recessive disorder caused by a deletion mapped to chromosome 17p13. The gene codes for a protein, cystinosin (CTNS), a lysosomal membrane transporter protein. When the CTNS gene is inactivated, the amino acid cystine cannot cross the lysosomal membrane and accumulates in lysosomes. Thus, cystinosis is a lysosomal storage disease. The accumulated cystine forms crystals that can cause damage to multiple organs. Cystinosis is thought to occur with an incidence of 1 in 100,000 live births, although accurate numbers are difficult to obtain because the disease may remain undiagnosed. Cystinosis was first described as a renal tubular disorder in the early 20th century by Fanconi and others (see Gahl et al. 2002 for a review). In 1967, accumulation of cystine within cells was recognized, and the lysosomal transport defect was identified in 1982. The first signs and symptoms of cystinosis are caused by renal tubular dysfunction, with the Fanconi syndrome developing within the first few months of life. Infants develop polyuria, dehydration, vomiting, poor appetite, and excessive thirst. If not recognized and treated early, these infants have failure to thrive and may develop rickets. The diagnosis can be made by assaying the cystine concentration in white blood cells; a level of greater than 2 nmol half-cystine per milligram of protein is diagnostic. The gene can now be sequenced, but this is conducted primarily in research settings and is not readily available clinically. Once diagnosed, treatment with a cystine-depleting agent, cysteamine, can be introduced immediately. The natural history of untreated nephropathic cystinosis is that of progressive renal failure, with renal dialysis and ultimately kidney transplant typically being necessary by the age of 10 years. Even with successful renal transplantation, life expectancy is greatly shortened, with death typically in the third or fourth decade. The reason for the early mortality is that cystinosis affects multiple other organs besides the kidney, and renal transplantation does not prevent the other systemic complications. Although the most prominent manifestations of the disease are renal, other organs are involved to varying degrees.
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Manger, Bernhard. "Inherited metabolic diseases." In Oxford Textbook of Rheumatology, 1451–56. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0170.
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A variety of hereditary disorders can present with structural or functional alterations of the musculoskeletal system. In particular, genetic defects within enzymatic pathways involved in the lysosomal degradation of various substrates can manifest with bone or joint symptoms. Because musculoskeletal complaints are frequently the first reason for the patient to seek medical advice, the rheumatologist may play a crucial role in the early diagnosis of these diseases. Lysosomal storage diseases are a heterogeneous group of individually very rare disorders, but taken together they have a prevalence of more than 1 in 8000 live births. Some of these lysosomal storage diseases can nowadays be treated very effectively by enzyme replacement therapies; however, a timely start of treatment is essential to avoid irreversible organ damage and deterioration of the quality of life. Therefore, the rheumatologist should be able to recognize signs and symptoms of the most frequent treatable lysosomal storage diseases.
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Kåks, Ida, and Peter Magnusson. "Fabry Disease." In Cardiomyopathy - Disease of the Heart Muscle [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99142.
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Fabry disease (FD) is a lysosomal storage disorder where deficient or completely absent activity of the enzyme α-galactosidas A leads to accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes. The condition is rare, approximately 1:50,000, although underdiagnosis seems frequent. The condition can affect multiple organ systems, including the skin, nervous system, kidneys, and heart. Early manifestations include skin lesions (angiokeratoma), neuropathic pain, and gastrointestinal symptoms. Later on, FD can result in cardiomyopathy, kidney failure, and stroke. Both lifespan and health-related quality of life are affected negatively by FD. Patients are divided into a classical or a non-classical phenotype based on presentation, where the diagnosis of classical FD requires that a set of specific criteria are met. Patients with non-classical FD often have a less severe disease course, sometimes limited to one organ. The hereditary pattern is X-linked. Thus, men are in general more severely affected than women, although there is an overlap in symptomatic burden. Two types of specific treatment options are available: enzyme replacement therapy and pharmacological chaperone therapy. In addition to this, management of each organ manifestation with usual treatment is indicated.
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Hoover, Kevin B. "Lipidoses." In Musculoskeletal Imaging Volume 2, edited by Kevin B. Hoover, 73–78. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780190938178.003.0083.
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Chapter 83 discusses lipidoses. The lipidoses are genetic diseases caused by enzyme deficiencies, which result in the cellular accumulation of lipids. These abnormal cells infiltrate tissues, including bone marrow, resulting in their dysfunction. Gaucher disease (GD) is the most common lysosomal storage disease (LSD) and lipidosis. Fabry disease (FD) is an X-linked recessive disease. Together, GD and FD account for 20% of LSDs. Nonspecific bone changes are detected using radiography, however, MRI is the most useful modality to evaluate involvement of the bone and bone marrow. MRI can also be used to detect treatment response. Enzyme replacement therapy (ERT) is the primary treatment for GD.
Conference papers on the topic "Ca2+ lysosomal"
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Athayde, C. M., and M. C. Scrutton. "ROLE OF GUANINE NUCLEOTIDES IN Ca2+ - DEPENDENT LYSOSOMAL SECRETION FROM ELECTROPERMEABILISED PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644513.
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Previous studies have shown that the maximal extent of Ca2+ dependent secretion of β-N-acetylglucosaminidase (B-N-AcGlc) from electropermeabilised human platelets can be enhanced by addition of thrombin or of 1-oleyl-2-acetylglycerol or 12-0-tetradecanoyl phorbol-13-acetate without a significant alteration in the EC^q for Ca2+. (Knight et al. Europ. J. Biochem.,143337 (1984)). We have found a similar Ca2+ dependent increase in the maximal extent of β-N-AcGlc and β-galactosidase secretion on addition of metabolically stable analogues of GTP (GTPγS and GppNHp) in the absence of thrombin or of GTP added in the presence of a nonsaturating concentration of thrombin. The EC50 values for GTP and GppNHp do not differ significantly for β-N-AcGlc and 3H-5HT secretion, but GTPγS is significantly more effective for 3H-5HT secretion.The time course of β-N-AcGlc secretion induced by GTPγS shows a significant delay as compared with that induced by thrombin + Ca2+. No significant differences could be detected between the properties of β-N-AcGlc or β-galactosidase secretion in this system. The results are consistent with involvement of a GTP binding protein (Np) in receptor-phospholipase C coupling mediating lysosomal secretion, but provide no indication that an additional protein of this type (Ne) is involved as has been proposed for lysosomal secretion from neutrophils. We have thus far failed to find evidence for heterogeneity in lysosomal secretion in this system (supported by SERC and Ciba-Geigy).
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Kallunki, Tuula, Ditte M. Brix, Bo Rafn, Knut Kristoffer Bundgaard Clemmensen, Sofie Hagel Andersen, Noona Ambartsumian, and Marja Jäättelä. "Abstract 3149: Targeting ERBB2-induced, lysosome-mediated invasion." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-3149.
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Kohli, Latika, Steven L. Carroll, and Kevin A. Roth. "Abstract A33: Pan erbB inhibition enhances lysosomal dysfunction-induced death in malignant peripheral nerve sheath tumor cells." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a33.
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Marchand, Benoît, Alexandre Raymond-Fleury, and Marie-Josée Boucher. "Abstract 315: Regulation of the transcription factor TFEB and the autophagic/lysosomal network by GSK3 in pancreatic cancer cells." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-315.
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Patscheke, H., and G. Mathieu. "MONITORING OF THE PLATELET ALPHA-GRANULE SECRETION IN THE AGGREGOMETER." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643492.
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If platelets are stimulated to secrete and the aggregation is prevented by EDTA and no stirring, the optical density (OD) decreases as a consequence of secretion (Patscheke et al. Thromb. Res. 33: 314, 1984). The purpose of this study was to determine which secretory compartment causes the change in OD and to analyze the quantitative relationship between decrease in OD and granule discharge. Human washed platelets were stimulated with thrombin and A 23187 in a Lumi-Aggregometer (Chrono-Log) which permitted simultaneous recording of the change in OD and of the ATP release from dense granules. At various time intervals, platelet factor 4 (PF-4), [3H)serotonin (5-HT), 8-N-ace-tylglucosaminidase (NAG) and lactate dehydrogenase (LDH) were determined in the supernatant as parameters of the release from the alpha granules, dense granules, lysosomes and the cytoplasm, respectively. In order to prevent the platelet shape change (increase in OD) from interfering with secretion (decrease in OD), the platelets were pretreated with 0.1 nM PAF 2 min prior to the secretagogue. PAF induced the shape change but no release of platelet constituents. The results show that the decrease in OD closely correlates with the release of PF-4. The fractional effects were identical in concentration-effect and time-effect studies. However, neither the decrease in OD nor the release of PF-4 were correlated with the release of ATP and 5-HT from the dense granules or the lysosomal release of NAG. The release of ATP and 5-HT required significantly higher agonist concentrations than the decrease in OD and the release of PF-4 and even higher concentrations were required for the release of NAG. LDH liberation did not exceed 1 % with 1 U/ml thrombin, indicating the absence of lysis. Thrombin 1 U/ml caused a maximum decrease in OD of 11 % and 40 % release of PF-4. In a patient with gray platelet syndrome, the decrease in OD was absent while the release of 5-HT was normal. These results show that the decrease in OD is due to alpha-granule secretion. The turbidimetric method offers a valuable tool for kinetic measurements of alpha-granule secretion. By using a Lumi-Aggregometer, secretion from alpha and dense granules can be monitored simultaneously. (Supported by the Deutsche Forschungsgemeinschaft, Grant Pa-263).
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Krželj, Vjekoslav, and Ivana Čulo Čagalj. "INHERITED METABOLIC DISORDERS AND HEART DISEASES." In Symposium with International Participation HEART AND … Akademija nauka i umjetnosti Bosne i Hercegovine, 2019. http://dx.doi.org/10.5644/pi2019.181.02.
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Inherited metabolic disorders can cause heart diseases, cardiomyopathy in particular, as well as cardiac arrhythmias, valvular and coronary diseases. More than 40 different inherited metabolic disorders can provoke cardiomyopathy, including lysosomal storage disorders, fatty acid oxidation defects, organic acidemias, amino acidopathies, glycogen storage diseases, congenital disorders of glycosylation as well as peroxisomal and mitochondrial disorders. If identified and diagnosed on time, some of congenital metabolic diseases could be successfully treated. It is important to assume them in cases when heart diseases are etiologically undefined. Rapid technological development has made it easier to establish the diagnosis of these diseases. This article will focus on common inherited metabolic disorders that cause heart diseases, as well as on diseases that might be possible to treat.
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Zhao, Ting, Hong Du, Xinchun Ding, Katlin Walls, and Cong Yan. "Abstract 161: Activation of mTOR pathway in myeloid-derived suppressor cells with lysosomal acid lipase deficiency stimulates cancer cell proliferation and metastasis." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-161.
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El-Osta, Hazem, Samantha Dykes, Jennifer Carroll, Floyd Galiano, and James Cardelli. "Abstract B5: A novel high-content screening approach to identify inhibitors of lysosome anterograde trafficking and tumor invasion." In Abstracts: AACR Special Conference on Tumor Invasion and Metastasis - January 20-23, 2013; San Diego, CA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.tim2013-b5.
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El-Osta, Hazem E., Samantha Dykes, Magdalena Circu, Jennifer Carroll, Kinsey Kelly, Floyd Galiano, Glenn Mills, and James Cardelli. "Abstract 4065: A novel imaging-based high-throughput assay identifies Niclosamide as inhibitor of lysosome anterograde trafficking and tumor invasion." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-4065.
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Purdon, A. D., and J. B. Smith. "ISOLATION OF A SOLUBLE PHOSPHOLIPASE A2 FROM HUMAN PLATELETS ACTIVE AGAINST 1-ACYL-2-ARACHIDONOYL GLYCEROPHOSPHOCHOLINE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644628.
Full textAbstract:
Previously, we have shown that 1-acyl-2-arachidonoyl glycero-phosphocholine (GPC) is the main source of arachidonic acid in thrombin-stimulated (5 U/ml) human platelets. Thus 1-acyl-2-3H-arachidonoyl GPC was dispersed in Tris buffer, 0.01 M, pH 7.5, 0.01 M CaCl2 for use a substrate for the assay of phospholipase A2 activity in human platelets. The released 3H-arachidonate(AA) was isolated by thin layer chromatography following Bligh and Dyer extraction of the enzyme-substrate incubate. Phospholipase A2 (PLA2) specific for this phospholipid was thought to be membrane bound and of low activity when solubilized, however, we have found, that provided resting platelets are gently sonicated while suspended in tyrode's buffer in the presence of suitable concentrations of protease inhibitors and metal chelators (EGTA, EDTA), a large amount of soluble PLA2 activity can be isolated following centrifugation to remove membranes. The enzyme required calcium for activity and was inactive in the presence of EGTA. No activity was found in the secretate from thrombin-stimulated cells, indicating that the PLA2 assayed at pH 7.5 was not lysosomal. PLA2 was further purified by DEAE cellulose chromatography where a 5 times increase in specific activity was achieved. It is known that OAG (1-oleoyl-2-acetyle-glycerol) augments deacylation of 1,2 diradyl GPC in platelets stimulated with suboptimal levels of ionophore A23187. Thus the effect of OAG stimulation of platelets on the distribution of soluble PLA2 was studied. Platelets (109 cells/ml) suspended in tyrode's buffer and stimulated with 100 ug/ml OAG or 5 U/ml thrombin (10 min, 37°C., 10 min, without stirring), showed a considerable decrease in soluble PLA2 activity suggesting a partitioning of soluble PLA2 into the membrane bilayer. Thus a model for PLA2 action is suggested in which binding of the cytosolic enzyme to its site of hydrolysis is induced by diglyceride-perturbation of the membrane, phospholipid, bilayer phase.