Sortilin expression and uptake of α-galactosidase A: A general mechanism of endocytosis in Fabry disease cell types

Epithelial cells exfoliated in human urine can include cells anywhere from the urinary tract and kidneys; however, podocytes and proximal tubular epithelial cells (PTECs) are by far the most relevant cell types for the study of genetic kidney diseases. When maintained in vitro, they have been proven extremely valuable for discovering disease mechanisms and for the development of new therapies. Furthermore, cultured patient cells can individually represent their human sources and their specific variants for personalized medicine studies, which are recently gaining much interest. In this review, we summarize the methodology for establishing human podocyte and PTEC cell lines from urine and highlight their importance as kidney disease cell models. We explore the well-established and recent techniques of cell isolation, quantification, immortalization and characterization, and we describe their current and future applications.

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CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M)

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-3910 ◽

2018 ◽

Vol 40 (4) ◽

pp. 333-338

Author(s):

Ester Miranda Pereira ◽

Adalberto Socorro da Silva ◽

Raimundo Nonato da Silva ◽

José Tiburcio Monte Neto ◽

Fernando F. do Nascimento ◽

...

Keyword(s):

Fabry Disease ◽

Cell Types ◽

Control Group ◽

Gene Encoding ◽

Peripheral Blood Mononuclear ◽

Enzyme Replacement ◽

Replacement Treatment ◽

Promising Tool ◽

Potential Marker ◽

Different Cell Types

ABSTRACT Introduction: Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT). Objective: The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). Methods: We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types. Results: A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels. Conclusion: The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

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Patient-specific Fabry disease cell models as a tool to evaluate the amenability to chaperone therapy

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2018.12.231 ◽

2019 ◽

Vol 126 (2) ◽

pp. S93

Author(s):

Malte Lenders ◽

Franciska Stappers ◽

Christoph Niemietz ◽

Boris Schmitz ◽

Andree Zibert ◽

...

Keyword(s):

Fabry Disease ◽

Patient Specific ◽

Cell Models ◽

Disease Cell

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Kiss-and-Coat and Compartment Mixing: Coupling Exocytosis to Signal Generation and Local Actin Assembly

Molecular Biology of the Cell ◽

10.1091/mbc.e05-10-0908 ◽

2006 ◽

Vol 17 (4) ◽

pp. 1495-1502 ◽

Cited By ~ 60

Author(s):

Anna M. Sokac ◽

William M. Bement

Keyword(s):

Cell Types ◽

Secretory Vesicle ◽

Signal Generation ◽

General Mechanism ◽

Fusion Pore ◽

Secretory Vesicles ◽

Actin Assembly ◽

Vesicle Membrane ◽

Regulated Exocytosis ◽

Broad Variety

Regulated exocytosis is thought to occur either by “full fusion,” where the secretory vesicle fuses with the plasma membrane (PM) via a fusion pore that then dilates until the secretory vesicle collapses into the PM; or by “kiss-and-run,” where the fusion pore does not dilate and instead rapidly reseals such that the secretory vesicle is retrieved almost fully intact. Here, we describe growing evidence for a third form of exocytosis, dubbed “kiss-and-coat,” which is characteristic of a broad variety of cell types that undergo regulated exocytosis. Kiss-and-coat exocytosis entails prolonged maintenance of a dilated fusion pore and assembly of actin filament (F-actin) coats around the exocytosing secretory vesicles followed by direct retrieval of some fraction of the emptied vesicle membrane. We propose that assembly of the actin coats results from the union of the secretory vesicle membrane and PM and that this compartment mixing represents a general mechanism for generating local signals via directed membrane fusion.

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The octamer/mu E4 region of the immunoglobulin heavy-chain enhancer mediates gene repression in myeloma x T-lymphoma hybrids.

Molecular and Cellular Biology ◽

10.1128/mcb.13.6.3530 ◽

1993 ◽

Vol 13 (6) ◽

pp. 3530-3540 ◽

Cited By ~ 11

Author(s):

L Shen ◽

S Lieberman ◽

L A Eckhardt

Keyword(s):

B Cells ◽

Heavy Chain ◽

Gene Activation ◽

Immunoglobulin Heavy Chain ◽

Cell Types ◽

Single Copy ◽

Gene Repression ◽

General Mechanism ◽

E4 Region ◽

T Lymphoma

We have shown previously that the immunoglobulin heavy-chain enhancer acts as a repressor of gene transcription in hybrids between immunoglobulin-producing myelomas and a T-lymphoma line. We have now mapped this repressive activity to a 51-bp enhancer subfragment which contains the octamer and mu E4 protein-binding motifs. Even a single copy of this subfragment will repress gene expression in hybrid cells. Mutational analyses of the repressor fragment suggest that in non-B cells, a strong transcriptional repressor(s) functions through the same motifs important for gene activation in B cells. Changes in chromatin structure that accompany reporter gene repression suggest a general mechanism for prohibiting immunoglobulin heavy-chain locus activation in inappropriate cell types.

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Rapid Modulation of Aromatase Activity in the Vertebrate Brain

Journal of Experimental Neuroscience ◽

10.4137/jen.s11268 ◽

2013 ◽

Vol 7 ◽

pp. JEN.S11268 ◽

Cited By ~ 12

Author(s):

Thierry D. Charlier ◽

Charlotte A. Cornil ◽

Jacques Balthazart

Keyword(s):

Amino Acids ◽

Enzymatic Activity ◽

Kinase Inhibitors ◽

Cell Types ◽

Protein Kinase Inhibitors ◽

Site Directed Mutagenesis ◽

General Mechanism ◽

Aromatase Activity ◽

Vertebrate Brain ◽

Rapid Modulation

Numerous steroid hormones, including 17β-estradiol (E2), activate rapid and transient cellular, physiological, and behavioral changes in addition to their well-described genomic effects. Aromatase is the key-limiting enzyme in the production of estrogens, and the rapid modulation of this enzymatic activity could produce rapid changes in local E2 concentrations. The mechanisms that might mediate such rapid enzymatic changes are not fully understood but are currently under intense scrutiny. Recent studies in our laboratory indicate that brain aromatase activity is rapidly inhibited by an increase in intracellular calcium concentration resulting from potassium-induced depolarization or from the activation of glutamatergic receptors. Phosphorylating conditions also reduce aromatase activity within minutes, and this inhibition is blocked by the addition of multiple protein kinase inhibitors. This rapid modulation of aromatase activity by phosphorylating conditions is a general mechanism observed in different cell types and tissues derived from a variety of species, including human aromatase expressed in various cell lines. Phosphorylation processes affect aromatase itself and do not involve changes in aromatase protein concentration. The control of aromatase activity by multiple kinases suggests that several amino acids must be concomitantly phosphorylated to modify enzymatic activity but site-directed mutagenesis of several amino acids alone or in combination has not to date revealed the identity of the targeted residue(s). Altogether, the phosphorylation processes affecting aromatase activity provide a new general mechanism by which the concentration of estrogens can be rapidly altered in the brain.

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Regulation of Ca2+-release-activated Ca2+ current (Icrac) by ryanodine receptors in inositol 1,4,5-trisphosphate-receptor-deficient DT40 cells

Biochemical Journal ◽

10.1042/bj3600017 ◽

2001 ◽

Vol 360 (1) ◽

pp. 17-22 ◽

Cited By ~ 29

Author(s):

Kirill KISELYOV ◽

Dong Min SHIN ◽

Nikolay SHCHEYNIKOV ◽

Tomohiro KUROSAKI ◽

Shmuel MUALLEM

Keyword(s):

Time Course ◽

Ryanodine Receptors ◽

Cell Types ◽

Ruthenium Red ◽

General Mechanism ◽

Inward Rectification ◽

Wild Type ◽

Ip3 Receptor ◽

Inositol 1,4,5 Trisphosphate ◽

Dt40 Cells

Persistence of capacitative Ca2+ influx in inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-deficient DT40 cells (DT40IP3R-/−) raises the question of whether gating of Ca2+-release activated Ca2+ current (Icrac) by conformational coupling to Ca2+-release channels is a general mechanism of gating of these channels. In the present work we examined the properties and mechanism of activation of Icrac Ca2+ current in wild-type and DT40IP3R-/− cells. In both cell types passive depletion of internal Ca2+ stores by infusion of EGTA activated a Ca2+ current with similar characteristics and time course. The current was highly Ca2+-selective and showed strong inward rectification, all typical of Icrac. The activator of ryanodine receptor (RyR), cADP-ribose (cADPR), facilitated activation of Icrac, and the inhibitors of the RyRs, 8-N-cADPR, ryanodine and Ruthenium Red, all inhibited Icrac activation in DT40IP3R-/− cells, even after complete depletion of intracellular Ca2+ stores by ionomycin. Wild-type and DT40IP3R-/− cells express RyR isoforms 1 and 3. RyR levels were adapted in DT40IP3R-/− cells to a lower RyR3/RyR1 ratio than in wild-type cells. These results suggest that IP3Rs and RyRs can efficiently gate Icrac in DT40 cells and explain the persistence of Icrac gating by internal stores in the absence of IP3Rs.

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Mechanism for the Universal Pattern of Activity in Developing Neuronal Networks

Journal of Neurophysiology ◽

10.1152/jn.00857.2009 ◽

2010 ◽

Vol 103 (4) ◽

pp. 2208-2221 ◽

Cited By ~ 17

Author(s):

Joël Tabak ◽

Michael Mascagni ◽

Richard Bertram

Keyword(s):

Network Architecture ◽

Mean Field ◽

Cell Types ◽

Synaptic Depression ◽

General Mechanism ◽

Silent Interval ◽

Mean Field Model ◽

Correlation Pattern ◽

The Right ◽

Episodic Activity

Spontaneous episodic activity is a fundamental mode of operation of developing networks. Surprisingly, the duration of an episode of activity correlates with the length of the silent interval that precedes it, but not with the interval that follows. Here we use a modeling approach to explain this characteristic, but thus far unexplained, feature of developing networks. Because the correlation pattern is observed in networks with different structures and components, a satisfactory model needs to generate the right pattern of activity regardless of the details of network architecture or individual cell properties. We thus developed simple models incorporating excitatory coupling between heterogeneous neurons and activity-dependent synaptic depression. These models robustly generated episodic activity with the correct correlation pattern. The correlation pattern resulted from episodes being triggered at random levels of recovery from depression while they terminated around the same level of depression. To explain this fundamental difference between episode onset and termination, we used a mean field model, where only average activity and average level of recovery from synaptic depression are considered. In this model, episode onset is highly sensitive to inputs. Thus noise resulting from random coincidences in the spike times of individual neurons led to the high variability at episode onset and to the observed correlation pattern. This work further shows that networks with widely different architectures, different cell types, and different functions all operate according to the same general mechanism early in their development.

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Filopodia rotate and coil by actively generating twist in their actin shaft

10.21203/rs.3.rs-81906/v1 ◽

2020 ◽

Author(s):

Natascha Leijnse ◽

Younes Barooji ◽

Bram Verhagen ◽

Lena Wullkopf ◽

Janine Erler ◽

...

Keyword(s):

Cell Types ◽

Narrow Channel ◽

Eukaryotic Cell ◽

General Mechanism ◽

Specific Cell ◽

Filamentous Actin ◽

Cell Matrix ◽

Matrix Interactions ◽

Cell Matrix Interactions ◽

Different Cell Types

Abstract Filopodia are actin-rich structures, present on the surface of practically every known eukaryotic cell. These structures play a pivotal role in specific cell-cell and cell-matrix interactions by allowing cells to explore their environment, generate mechanical forces, perform chemical signaling, or convey signals via intercellular tunneling nano-bridges. The dynamics of filopodia appear quite complex as they exhibit a rich behavior of buckling, pulling, length and shape changes. Here, we find that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling of their actin rich core. Importantly, we show the rotational dynamics of the filamentous actin inside filopodia for a range of highly distinct and cognate cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist, and hence rotation, is an emergent phenomenon of active filaments confined in a narrow channel which points to a generic mechanism present in all cells. Our measurements confirm that filopodia exert traction forces and form helical buckles in a range of different cell types that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia

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