scholarly journals Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer

2005 ◽  
Vol 170 (1) ◽  
pp. 127-139 ◽  
Author(s):  
Bart Dermaut ◽  
Koenraad K. Norga ◽  
Artur Kania ◽  
Patrik Verstreken ◽  
Hongling Pan ◽  
...  
Keyword(s):  
Neuronal Degeneration ◽  
Dependent Manner ◽  
Lysosomal Storage ◽  
Cellular Mechanisms ◽  
Neuronal Viability ◽  
Vesicle Recycling ◽  
Carbohydrate Storage ◽  
Functional Consequences ◽  
Larval Neuromuscular Junction ◽  
Dose Dependent

Lysosomal storage is the most common cause of neurodegenerative brain disease in preadulthood. However, the underlying cellular mechanisms that lead to neuronal dysfunction are unknown. Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions. At the bnch larval neuromuscular junction, we observe similar inclusions and find defects in synaptic vesicle recycling at the level of endocytosis. In addition, loss of bnch slows endosome-to-lysosome trafficking in larval garland cells. In adult bnch flies, we observe age-dependent synaptic dysfunction and neuronal degeneration. Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner. We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.

A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1631-1639
Author(s):  
Yo Suzuki ◽  
Gail A Morris ◽  
Min Han ◽  
William B Wood
Keyword(s):  
Caenorhabditis Elegans ◽  
Body Shape ◽  
Small Body ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Gene Expression Analyses ◽  
Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

scholarly journals Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

2020 ◽  
Vol 21 (21) ◽  
pp. 7819
Author(s):  
Noelia Benetó ◽  
Lluïsa Vilageliu ◽  
Daniel Grinberg ◽  
Isaac Canals
Keyword(s):  
Heparan Sulfate ◽  
Disease Modeling ◽  
Neuronal Degeneration ◽  
Lysosomal Storage ◽  
Sanfilippo Syndrome ◽  
Therapeutic Approaches ◽  
Cellular Mechanisms ◽  
Cellular Models ◽  
Induced Pluripotent ◽  
Cellular Dysfunction

Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.

scholarly journals (-)-Englerin-A Has Analgesic and Anti-Inflammatory Effects Independent of TRPC4 and 5

2021 ◽  
Vol 22 (12) ◽  
pp. 6380
Author(s):  
João de Sousa Valente ◽  
Khadija M Alawi ◽  
Sabah Bharde ◽  
Ali A. Zarban ◽  
Xenia Kodji ◽  
...  
Keyword(s):  
Thermal Hyperalgesia ◽  
Dependent Manner ◽  
Drg Neurons ◽  
East African ◽  
Cellular Mechanisms ◽  
Analgesic Effects ◽  
Englerin A ◽  
Anti Inflammatory ◽  
Dose Dependent

Recently, we found that the deletion of TRPC5 leads to increased inflammation and pain-related behaviour in two animal models of arthritis. (-)-Englerin A (EA), an extract from the East African plant Phyllanthus engleri has been identified as a TRPC4/5 agonist. Here, we studied whether or not EA has any anti-inflammatory and analgesic properties via TRPC4/5 in the carrageenan model of inflammation. We found that EA treatment in CD1 mice inhibited thermal hyperalgesia and mechanical allodynia in a dose-dependent manner. Furthermore, EA significantly reduced the volume of carrageenan-induced paw oedema and the mass of the treated paws. Additionally, in dorsal root ganglion (DRG) neurons cultured from WT 129S1/SvIm mice, EA induced a dose-dependent cobalt uptake that was surprisingly preserved in cultured DRG neurons from 129S1/SvIm TRPC5 KO mice. Likewise, EA-induced anti-inflammatory and analgesic effects were preserved in the carrageenan model in animals lacking TRPC5 expression or in mice treated with TRPC4/5 antagonist ML204.This study demonstrates that while EA activates a sub-population of DRG neurons, it induces a novel TRPC4/5-independent analgesic and anti-inflammatory effect in vivo. Future studies are needed to elucidate the molecular and cellular mechanisms underlying EA’s anti-inflammatory and analgesic effects.

scholarly journals RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 245
Author(s):  
So-Young Kim ◽  
Samel Park ◽  
Seong-Woo Lee ◽  
Ji-Hye Lee ◽  
Eun Soo Lee ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Kidney Injury ◽  
Ros Generation ◽  
Dependent Manner ◽  
Lysosomal Storage ◽  
Cellular Mechanisms ◽  
Cell Death Pathways ◽  
Fabry Nephropathy

Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients’ morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK’872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.

Cellular mechanisms of vasopressin and endothelin to mobilize [Mg2+]i in vascular smooth muscle cells

1992 ◽  
Vol 263 (4) ◽  
pp. C873-C878 ◽  
Author(s):  
K. Okada ◽  
S. Ishikawa ◽  
T. Saito
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Peak Level ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Indicator Dye ◽  
Dose Dependent

The present study was undertaken to examine the effects of arginine vasopressin (AVP) and endothelin-1 (ET-1) on cytosolic free Mg2+ ([Mg2+]i) in cultured rat vascular smooth muscle cells (VSMC). [Mg2+]i was measured using the fluorescence indicator dye mag-fura-2. AVP and ET-1 at a concentration of 1 x 10(-9) M or higher induced the mobilization of [Mg2+]i and cytosolic free Ca2+ ([Ca2+]i) in a dose-dependent manner in rat VSMC. Atrial natriuretic peptide and sodium nitroprusside producing cellular guanosine 3',5'-cyclic monophosphate did not affect [Mg2+]i and [Ca2+]i. A diterpene activator of adenylate cyclase, forskolin, also did not alter [Mg2+]i and [Ca2+]i. The removal of extracellular Mg2+ enhanced the AVP-mobilized [Ca2+]i and did not change the AVP-mobilized [Mg2+]i. The Ca(2+)-free and nominally Mg2+/Ca(2+)-free states decreased the AVP-mobilized [Mg2+]i and [Ca2+]i. The Na(+)-free state enhanced the sustained, but not peak, level of the AVP-mobilized [Mg2+]i. These results indicate that AVP and ET-1 mobilize [Mg2+]i mediated through their intracellular second messenger [Ca2+]i and independent of extracellular Mg2+. Also, an increase in [Mg2+]i is indicated to stimulate the Na(+)-Mg2+ exchange to increase cellular Mg2+ efflux.

Inhibition of NMDA Receptors Underlies the Neuroprotective Effect of Ginsenoside Rb3

2009 ◽  
Vol 37 (04) ◽  
pp. 759-770 ◽  
Author(s):  
Liang-Liang Peng ◽  
Hong-Mei Shen ◽  
Zheng-Lin Jiang ◽  
Xia Li ◽  
Guo-Hua Wang ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Nmda Receptors ◽  
Hippocampal Neurons ◽  
Neuroprotective Effect ◽  
Dependent Manner ◽  
Laser Confocal Microscopy ◽  
Patch Clamp Technique ◽  
Neuronal Viability ◽  
Nmda Current ◽  
Dose Dependent

In order to investigate the mechanisms underlying the neuroprotective effect of ginsenoside Rb 3, rat hippocampal neurons were primarily cultured, and exposed to 1 mM N-methyl-D-aspartate (NMDA), cell viability and lactate dehydrogenase leakage were measured. Ca 2+ influx was determined by calcium imaging with a laser confocal microscopy. The influences of ginsenoside Rb 3 on these variables were examined. Patch-clamp technique was used to observe the effects of ginsenoside Rb 3 on NMDA-evoked current. The results show that treatment of Rb 3 raised the neuronal viability, reduced the leakage of lactate dehydrogenase, and inhibited NMDA-elicited Ca 2+ influx in a dose-dependent manner. In the presence of Rb 3, NMDA-evoked peak current was inhibited, and Ca 2+-induced desensitization of NMDA current was facilitated. It is suggested that ginsenoside Rb 3 could exert a neuroprotective role on hippocampal neurons, a role which was partly mediated by the facilitation of Ca 2+-dependent deactivation of NMDA receptors, and the resultant reduction of intracellular free Ca 2+ level.

Effects of Low Molecular Weight Heparin and Unfragmented Heparin on Induction of Osteoporosis in Rats

1990 ◽  
Vol 63 (03) ◽  
pp. 505-509 ◽  
Author(s):  
Thomas Mätzsch ◽  
David Bergqvist ◽  
Ulla Hedner ◽  
Bo Nilsson ◽  
Per Østergaar
Keyword(s):  
Molecular Weight ◽  
Bone Mineral ◽  
Low Molecular Weight Heparin ◽  
Zinc Content ◽  
Low Molecular Weight ◽  
Dependent Manner ◽  
Bone Mineral Mass ◽  
Bone Ash ◽  
Dose Dependent ◽  
Mineral Mass

SummaryA comparison between the effect of low molecular weight heparin (LMWH) and unfragmented heparin (UH) on induction of osteoporosis was made in 60 rats treated with either UH (2 IU/ g b w), LMWH in 2 doses (2 Xal U/g or 0.4 Xal U/g) or placebo (saline) for 34 days. Studied variables were: bone mineral mass in femora; fragility of humera; zinc and calcium levels in serum and bone ash and albumin in plasma. A significant reduction in bone mineral mass was found in all heparin-treated rats. There was no difference between UH and LMWH in this respect. The effect was dose-dependent in LMWH-treated animals. The zinc contents in bone ash were decreased in all heparin-treated rats as compared with controls. No recognizable pattern was seen in alterations of zinc or calcium in serum. The fragility of the humera, tested as breaking strength did not differ between treatment groups and controls. In conclusion, if dosed according to similar factor Xa inhibitory activities, LMWH induces osteoporosis to the same extent as UH and in a dose-dependent manner. The zinc content in bone ash was decreased after heparin treatment, irrespective of type of heparin given.

Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

1996 ◽  
Vol 76 (01) ◽  
pp. 111-117 ◽  
Author(s):  
Yasuto Sasaki ◽  
Junji Seki ◽  
John C Giddings ◽  
Junichiro Yamamoto
Keyword(s):  
Blood Flow ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Red Cell ◽  
Cell Velocity ◽  
Red Cell Velocity ◽  
The Mean ◽  
Wall Shear ◽  
Dose Dependent

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

Melatonin actions in the heart; more than a hormone

2018 ◽  
Vol 1 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Darío Acuña-Castroviejo ◽  
Maria T Noguiera-Navarro ◽  
Russel J Reiter ◽  
Germaine Escames
Keyword(s):  
Cell Membranes ◽  
Myocardial Cell ◽  
Rat Tissues ◽  
Dependent Manner ◽  
Broad Distribution ◽  
Multiple Organs ◽  
High Doses ◽  
Extrapineal Melatonin ◽  
Dose Dependent ◽  
Different Doses

Due to the broad distribution of extrapineal melatonin in multiple organs and tissues, we analyzed the presence and subcellular distribution of the indoleamine in the heart of rats. Groups of sham-operated and pinealectomized rats were sacrificed at different times along the day, and the melatonin content in myocardial cell membranes, cytosol, nuclei and mitochondria, were measured. Other groups of control animals were treated with different doses of melatonin to monitor its intracellular distribution. The results show that melatonin levels in the cell membrane, cytosol, nucleus, and mitochondria vary along the day, without showing a circadian rhythm. Pinealectomized animals trend to show higher values than sham-operated rats. Exogenous administration of melatonin yields its accumulation in a dose-dependent manner in all subcellular compartments analyzed, with maximal concentrations found in cell membranes at doses of 200 mg/kg bw melatonin. Interestingly, at dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The results confirm previous data in other rat tissues including liver and brain, and support that melatonin is not uniformly distributed in the cell, whereas high doses of melatonin may be required for therapeutic purposes.

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