Papers by María-paz Marzolo
bioRxiv (Cold Spring Harbor Laboratory), Dec 21, 2023
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The EMBO Journal, Oct 4, 2011
Mutations in the phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2) 5-phosphatase OCRL cause Low... more Mutations in the phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2) 5-phosphatase OCRL cause Lowe syndrome, which is characterised by congenital cataracts, central hypotonia, and renal proximal tubular dysfunction. Previous studies have shown that OCRL interacts with components of the endosomal machinery; however, its role in endocytosis, and thus the pathogenic mechanisms of Lowe syndrome, have remained elusive. Here, we show that via its 5-phosphatase activity, OCRL controls early endosome (EE) function. OCRL depletion impairs the recycling of multiple classes of receptors, including megalin (which mediates protein reabsorption in the kidney) that are retained in engorged EEs. These trafficking defects are caused by ectopic accumulation of PtdIns4,5P2 in EEs, which in turn induces an N-WASP-dependent increase in endosomal F-actin. Our data provide a molecular explanation for renal proximal tubular dysfunction in Lowe syndrome and highlight that tight control of PtdIns4,5P2 and F-actin at the EEs is essential for exporting cargoes that transit this compartment.
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Molecular and Cellular Neuroscience, Apr 1, 2016
a Laboratorio de Tráfico Intracelular y Señalización, Departamento de Biología Celular y Molecula... more a Laboratorio de Tráfico Intracelular y Señalización, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile b Millennium Nucleus for Regenerative Biology, Santiago, Chile c Departmento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile d Laboratory of Neurobiology, Instituto Mercedes y Martin Ferreyra (INIMEC) CONICET, Córdoba, Argentina
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BMC Biology
Background Drosophila melanogaster lipophorin receptors (LpRs), LpR1 and LpR2, are members of the... more Background Drosophila melanogaster lipophorin receptors (LpRs), LpR1 and LpR2, are members of the LDLR family known to mediate lipid uptake in a range of organisms from Drosophila to humans. The vertebrate orthologs of LpRs, ApoER2 and VLDL-R, function as receptors of a glycoprotein involved in development of the central nervous system, Reelin, which is not present in flies. ApoER2 and VLDL-R are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain, as well as with neurodevelopmental and neurodegenerative disorders linked to those regions. It is currently unknown whether LpRs play similar roles in the Drosophila brain. Results We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the mushroom bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the com...
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Frontiers in Cell and Developmental Biology
Megalin/LRP2 is the primary multiligand receptor for the re-absorption of low molecular weight pr... more Megalin/LRP2 is the primary multiligand receptor for the re-absorption of low molecular weight proteins in the proximal renal tubule. Its function is significantly dependent on its endosomal trafficking. Megalin recycling from endosomal compartments is altered in an X-linked disease called Lowe Syndrome (LS), caused by mutations in the gene encoding for the phosphatidylinositol 5-phosphatase OCRL1. LS patients show increased low-molecular-weight proteins with reduced levels of megalin ectodomain in the urine and accumulation of the receptor in endosomal compartments of the proximal tubule cells. To gain insight into the deregulation of megalin in the LS condition, we silenced OCRL1 in different cell lines to evaluate megalin expression finding that it is post-transcriptionally regulated. As an indication of megalin proteolysis, we detect the ectodomain of the receptor in the culture media. Remarkably, in OCRL1 silenced cells, megalin ectodomain secretion appeared significantly reduc...
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<p>(<b>A</b>) HEK 293 cells were transfected with different myc-tagged SNX17 co... more <p>(<b>A</b>) HEK 293 cells were transfected with different myc-tagged SNX17 constructs, and their lysates were used for GST pull-down assays using GST or GST-ApoER2. The presence of SNX17 was evaluated by western blot with an anti-myc antibody. GST fusion proteins were detected by western blot using anti-GST antibody. F1, F2 and F3 indicates the three subdomains or modules of the FERM domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093672#pone.0093672-Ghai1" target="_blank">[35]</a>.(<b>B</b>) HEK 293 cells were transfected with HA-ApoER2 wild-type or mutated (NPxY/A) constructs. Cell lysates were used for a pull-down assay using GST or GST-SNX17. The receptor was evaluated by detecting the HA epitope. In both cases, Lys corresponds to 10% of the cell lysate used for the pull-down assay. (C) Cell extracts obtained from cells transiently transfected with myc-SNX17 and HA-ApoER2 were immunoprecipitated with anti-myc and probed for ApoER2 with the anti-HA antibody. Lys corresponds to 2% of the cell lysate used for the coinmunoprecipitation. (<b>D</b>) HeLa cells were transfected with HA-ApoER2, RAP, and myc-SNX17. Cells were incubated with anti-HA antibody for 1 h at 4°C, and receptor internalization was allowed for 10 min at 37°C. Cells were fixed and analyzed by immunofluorescence. Bar, 10 μm.</p
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Drosophila melanogaster Lipophorin Receptors, LpR1 and LpR2, mediate lipid uptake. The orthologs ... more Drosophila melanogaster Lipophorin Receptors, LpR1 and LpR2, mediate lipid uptake. The orthologs of these receptors in vertebrates, ApoER2 and VLDL-R, bind Reelin, a glycoprotein not present in flies. These receptors are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain. It is currently unknown whether LpRs play similar roles in the Drosophila brain. We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the Mushroom Bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurites. This effect depends on LpRs and Dab, the Drosophila ortholog of the reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin. Overall, these findings demonstrate that LpRs contribute to MB de...
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Journal of Lipid Research, 1989
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Journal of Neuroscience Research, 2020
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Megalin/LRP2 is a receptor that plays important roles in the physiology of several organs, such a... more Megalin/LRP2 is a receptor that plays important roles in the physiology of several organs, such as kidney, lung, intestine, and gallbladder; and also in the physiology of the nervous system. Megalin expression is reduced in diseases associated with fibrosis, including diabetic nephropathy, hepatic fibrosis and cholelithiasis, as well as in some breast and prostate cancers. One of the hallmarks of these conditions is the presence of the cytokine transforming growth factor beta (TGF-ß). Although TGF-ß has been implicated in the reduction of megalin levels, the molecular mechanism underlying this regulation is not well understood. Here, we show that treatment of two epithelial cell lines (from kidney and gallbladder) with TGF-ß1 is associated with decreased megalin mRNA and protein levels, and that these effects are reversed by inhibiting the TGF-ß1 type I receptor (TGF-ßRI). Based onin silicoanalyses, the two SMAD-binding elements (SBEs) in the megalin promoter are located at position...
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Molecular and Cellular Neuroscience, 2015
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Archivos de biología y medicina experimentales, 1989
The liver represents the principal pathway for sterol excretion from the organism. In addition, t... more The liver represents the principal pathway for sterol excretion from the organism. In addition, the major proportion of serum lipoproteins is catabolized in the liver. It is known that diosgenin and bean diet markedly induce biliary cholesterol output. In this series of studies we characterized the catabolism of several lipoprotein particles in animals fed diosgenin or a bean-rich diet (biliary cholesterol output is increased greater than 300% in these animals). Human low density lipoprotein (hLDL) and rat high density lipoprotein apo-E free (rHDL) were labeled with 125I. Rat chylomicrons were labeled with cholesterol-(3H)-oleate. hLDL clearance increased from 381 +/- 39 to 628 +/- 44 (microliters/h x 100 g body wt) (p less than 0.005) in bean-fed rats. The half life (t1/2) decreased from 12.4 +/- 1 to 9.8 +/- 0.7 h (p less than 0.005) in these rats. The clearance of rHDL apo-E free increased from 579 +/- 8 to 680 +/- 36 (microliters/h x 100 g body wt) (p less than 0.05) in diosgeni...
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Hepatology (Baltimore, Md.), 1990
A significant amount of biliary cholesterol is carried in unilamellar-phospholipid (lecithin) ves... more A significant amount of biliary cholesterol is carried in unilamellar-phospholipid (lecithin) vesicles, in both supersaturated human hepatic bile and unsaturated rat bile. This fact supports the concept that biliary cholesterol is normally secreted in phospholipid vesicles from the hepatocyte into the canaliculus. The fundamental aspects of biliary lipid secretion relate first to the quantitative determinants of hepatocytic cholesterol secretion into the bile and, second, to the cell biology of this process. There is a tight curvilinear coupling between the rates of bile acids and biliary lipid secretion in all animal species. The hydrophobicity of the bile acid pool may modify this cosecretory mechanism in that more hydrophobic bile acids recruit more phospholipid and cholesterol per mole of bile acid secreted into the bile. The quantitative significance of this effect, however, is relatively minor. In contrast, intrahepatic determinants, such as the rates of hepatic cholesterol es...
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Frontiers in Biology, 2012
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BMC Neuroscience, 2014
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Journal of Biological Chemistry, 2000
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Alzheimer's & Dementia, 2006
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<b>Copyright information:</b>Taken from "ApoER2 expression increases Aβ producti... more <b>Copyright information:</b>Taken from "ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity"http://www.molecularneurodegeneration.com/content/2/1/14Molecular Neurodegeneration 2007;2():14-14.Published online 9 Jul 2007PMCID:PMC1939850.or without saponin and then labeled with anti-APP antibody. Primary antibody was detected with PE-conjugated goat anti-mouse IgG. Values are the average of triplicate determinations. indicate S.E. , lysates were prepared from CHO-pcDNA3 and ApoER2-expressing cells and equal amounts of protein were subjected to 10% SDS-PAGE. Blots were probed with anti-HA and anti-β-tubulin antibodies.
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