The properties of acidic compartments in developing schistosomula of<i>Schistosoma mansoni</i>

Al-Adhami, Batol; Thornhill, J.; Akhkha, Abdellah; Doenhoff, Michael J.; Kusel, J. R.

doi:10.1017/s003118200300369x

Cited by 7 publications

(14 citation statements)

References 25 publications

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“…Almost all (95%) of Gleevec entering cells (regardless of cell type) becomes sequestered in lysosomes (25,26) through ion trapping, because Gleevec is a weak base (27)(28)(29). To examine the possibility that Gleevec might inhibit the activities of lysosomal proteases by raising lysosomal pH, we exposed N2a 695 cells to vehicle or to Gleevec for 4 h and then to the lysosomotropic dye Lysotracker Red (Thermo Fisher Scientific), which sequesters in acidified lysosomes (30). Gleevec pretreatment increased the amount of Lysotracker Red in lysosomes and also appeared to increase lysosomal volume (Fig.…”

Section: Resultsmentioning

confidence: 99%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

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Section: Resultsmentioning

confidence: 99%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Autophagy is a more feasible process than apoptosis for vitelline cell degradation because almost all of the autophagic components have been found in the transcriptome and autophagy is known to occur in adult schistosomes [42,44,45]. Autophagy eliminates unwanted cells during developmental cell death in various taxa, including the ovarian nurse cells in Bombyx mori and Ceratitis capitata [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

The proteasome-ubiquitin pathway in the Schistosoma mansoni egg has development- and morphology-specific characteristics

Mathieson

Castro-Borges

Wilson

2011

Molecular and Biochemical Parasitology

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Schistosoma mansoni eggs, consisting of an ovum surrounded by nutritive vitelline cells packaged in a tanned protein shell, are produced by paired worms residing in the mesenteric veins of the human host. The vitelline cells are degraded as the larval miracidium matures, the fully developed egg either crossing the gut wall to escape the host or becoming lodged in the host's tissues where it dies and disintegrates, inducing a potentially pathological immune response. Thus, the egg is central to both the transmission of the parasite and the aetiology of the disease. Here we present the first study investigating protein turnover in the egg. We establish that the ubiquitin-proteasome pathway (UPP) changes with egg development and furthermore, that the morphological components of the fully developed egg (the miracidium and the subshell envelope) also exhibit different proteasome subunit expression profiles. We conclude that the UPP is responsible not only for degrading the vitelline cells but is also more highly developed in the envelope than in the miracidium. The envelope is involved in the defence of the miracidium and produces the proteins that the egg secretes, presumably to facilitate its escape from the host, so the UPP probably has a multi-faceted role in the egg's biology.

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“…Carneiro-Santos et al (2001) demonstrated the presence of acidic organelles similar to lysosomes in schistosomula, as well as the absence of the same organelles in cercariae. These data were confirmed by Al-Adhami et al (2003, 2005. In this latter study, it was also demonstrated that miracidia do not reveal the presence of acidic vesicles when exposed to LysoTracker Red.…”

Section: Discussionmentioning

confidence: 55%

“…In studies using S. mansoni, Al-Adhami et al (2003) ally similar to lysosomes, in schistosomula, and the absence of them in cercariae, by means of the label Lyso Tracker Red, specific for lysosomes of mammal cells (Dietl et al 1996). In another study, Al-Adhami et al (2005) observed the presence of large acidic organelles in immature worms (lung stage), but not in adult worms and miracidia.…”

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confidence: 96%

Activity of praziquantel on in vitro transformed Schistosoma mansoni sporocysts

Mattos

Kusel

Pimenta

et al. 2006

Mem. Inst. Oswaldo Cruz

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Praziquantel (PZQ) is effective against all the evolutive phases of (Doenhoff et al. 2002). Nevertheless, the mechanisms of action of this drug against Schistosoma mansoni are not yet precisely clarified until now (Cioli & Picca-Mattoccia 2003). It is well known that PZQ is effective against all the evolutive phases of the parasite, being more active against cercariae and adult worms (Gonnert & Andrews 1977). Previous studies in our laboratory, as well as data from the literature, demonstrated that PZQ acts on the intramolluscan phase of Schistosoma interrupting cercarial shedding (Coles 1979, Touassem & Combes 1986, Yi & Combes 1987, Coelho et al. 1988, Riley & Chappell 1990.Morphological and physiological changes in S. mansoni under the effect of PZQ, at different evolutive phases of the parasite's life cycle, have been demonstrated using as a tool fluorescent labels. Oliveira et al. (2006) demonstrated that PZQ causes damages to the tegument of adult worms, and that these lesion sites are markedly labeled by the probe Hoechst 33258 (specific for DNA and being utilized as indicator of membrane integrity). However, the same lesions are not labelled by the probe lectin of Glycine max (specific for N-acetylgalactosamine, a carbohydrate present in the parasite tegument).In studies using S. mansoni, Al-Adhami et al. ally similar to lysosomes, in schistosomula, and the absence of them in cercariae, by means of the label Lyso Tracker Red, specific for lysosomes of mammal cells (Dietl et al. 1996). In another study, Al-Adhami et al. (2005) observed the presence of large acidic organelles in immature worms (lung stage), but not in adult worms and miracidia. Carneiro-Santos et al. (2001), besides reporting the presence of lysosomes in schistosomula, verified that PZQ interferes with the formation of acidic organelles. Thus, we evaluated in this work the presence of lysosomes in in vitro transformed S. mansoni sporocysts, as well as the activity of PZQ on those acidic organelles and on the parasite's tegument, by means of fluorescent labels. MATERIALS AND METHODSIn vitro transformation of sporocysts -Infected mice with S. mansoni cercariae (LE strain) were sacrificed after 50-day-infection. Their livers were collected and kept in sterile saline 0.85%, containing 10% antibiotics penicillin/ streptomycin (Sigma Chemical Co., St. Louis, MO, US), at room temperature, for 30 min. Afterwards, the livers were homogenized and washed to obtain miracidia, using sterile materials, according to the technique described by Pellegrino and Siqueira (1968). Miracidia were gathered into conic tubes of 50 ml and maintained on ice for 30 min. The supernatant was discarded and 5 ml liquid with miracidia were kept apart. Miracidia were cultured/transformed in culture medium RPMI-1640 pH 7.4 (Sigma) supplemented with 5% (v/v) inactivate fetal bovine serum (FBS) (Gibco Limited, Paisley, Scotland, UK) and 20 µg/ml antibiotic gentamicine in B.O.D., at 26 o C, for 24 h. Cultured medium (15 ml) was stored in bottles of 25cm 2 each, with addition o...

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The properties of acidic compartments in developing schistosomula ofSchistosoma mansoni

Cited by 7 publications

References 25 publications

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

The proteasome-ubiquitin pathway in the Schistosoma mansoni egg has development- and morphology-specific characteristics

Activity of praziquantel on in vitro transformed Schistosoma mansoni sporocysts

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