LIVIVO - Search results -

Search results

Result 1 - 10 of total 12

Search options

Book ; Online ; Thesis: Characterization of the physiological and pathophysiological role of the proteasome in glomerular cells

Sachs, Wiebke [Verfasser] / Brune, Wolfram [Akademischer Betreuer]

2020

Author's details	Wiebke Sachs ; Betreuer: Wolfram Brune
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Staats- und Universitätsbibliothek Hamburg
Publishing place	Hamburg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration.

Sachs, Wiebke / Blume, Lukas / Loreth, Desiree / Schebsdat, Lisa / Hatje, Favian / Koehler, Sybille / Wedekind, Uta / Sachs, Marlies / Zieliniski, Stephanie / Brand, Johannes / Conze, Christian / Florea, Bogdan I / Heppner, Frank / Krüger, Elke / Rinschen, Markus M / Kretz, Oliver / Thünauer, Roland / Meyer-Schwesinger, Catherine

Nature communications

2024 Volume 15, Issue 1, Page(s) 1897

Abstract: Kidney filtration is ensured by the interaction of podocytes, endothelial and mesangial cells. Immunoglobulin accumulation at the filtration barrier is pathognomonic for glomerular injury. The mechanisms that regulate filter permeability are unknown. ... ...

Abstract	Kidney filtration is ensured by the interaction of podocytes, endothelial and mesangial cells. Immunoglobulin accumulation at the filtration barrier is pathognomonic for glomerular injury. The mechanisms that regulate filter permeability are unknown. Here, we identify a pivotal role for the proteasome in a specific cell type. Combining genetic and inhibitor-based human, pig, mouse, and Drosophila models we demonstrate that the proteasome maintains filtration barrier integrity, with podocytes requiring the constitutive and glomerular endothelial cells the immunoproteasomal activity. Endothelial immunoproteasome deficiency as well as proteasome inhibition disrupt the filtration barrier in mice, resulting in pathologic immunoglobulin deposition. Mechanistically, we observe reduced endocytic activity, which leads to altered membrane recycling and endocytic receptor turnover. This work expands the concept of the (immuno)proteasome as a control protease orchestrating protein degradation and antigen presentation and endocytosis, providing new therapeutic targets to treat disease-associated glomerular protein accumulations.
MeSH term(s)	Mice ; Humans ; Animals ; Swine ; Proteasome Endopeptidase Complex ; Endothelial Cells ; Kidney Glomerulus/pathology ; Kidney Diseases/pathology ; Endocytosis ; Immunoglobulins
Chemical Substances	Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Immunoglobulins
Language	English
Publishing date	2024-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46273-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Article ; Online: Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.

Nature communications

2023 Volume 14, Issue 1, Page(s) 2114

Abstract: Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging ... ...

Abstract	Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.
MeSH term(s)	Animals ; Mice ; Glomerulonephritis, Membranous/genetics ; Kidney Glomerulus ; Podocytes ; Proteasome Endopeptidase Complex ; Ubiquitin ; Ubiquitin Thiolesterase/genetics
Chemical Substances	Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Ubiquitin ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
Language	English
Publishing date	2023-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37836-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Publisher Correction: Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.

Nature communications

2023 Volume 14, Issue 1, Page(s) 2453

Language	English
Publishing date	2023-04-28
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38206-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Thrombospondin Type 1 Domain-Containing 7A Localizes to the Slit Diaphragm and Stabilizes Membrane Dynamics of Fully Differentiated Podocytes.

Herwig, Johanna / Skuza, Sinah / Sachs, Wiebke / Sachs, Marlies / Failla, Antonio Virgilio / Rune, Gabriele / Meyer, Tobias N / Fester, Lars / Meyer-Schwesinger, Catherine

Journal of the American Society of Nephrology : JASN

2019 Volume 30, Issue 5, Page(s) 824–839

Abstract: Background: About 3%-5% of adults with membranous nephropathy have autoantibodies directed against thrombospondin type 1 domain-containing 7A (THSD7A), a podocyte-expressed transmembrane protein. However, the temporal and spatial expression of THSD7A ... ...

Abstract	Background: About 3%-5% of adults with membranous nephropathy have autoantibodies directed against thrombospondin type 1 domain-containing 7A (THSD7A), a podocyte-expressed transmembrane protein. However, the temporal and spatial expression of THSD7A and its biologic function for podocytes are unknown, information that is needed to understand the effects of THSD7A autoantibodies in this disease. Methods: Using a variety of microscopic techniques, we analyzed THSD7A localization in postnatal, adult, and autoantibody-injected mice as well as in human podocytes. We also analyzed THSD7A function in human podocytes using confocal microscopy; Western blotting; and adhesion and migration assays. Results: We found that THSD7A expression begins on glomerular vascularization with slit diaphragm formation in development. THSD7A localizes to the basal aspect of foot processes, closely following the meanders of the slit diaphragm in human and mice. Autoantibodies binding to THSD7A localize to the slit diaphragm. In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with decreased membrane activity of cytoskeletal regulators. We also found that, phenotypically, THSD7A expression in human podocytes is associated not only with increases in cell size, enhanced adhesion, and reduced detachment from collagen type IV-coated plates but also, with decreased ability to migrate. Conclusions: Our findings suggest that THSD7A functions as a foot process protein involved in the stabilization of the slit diaphragm of mature podocytes and that autoantibodies to THSD7A, on the basis of their localization, might structurally and functionally alter the slit diaphragm's permeability to protein.
MeSH term(s)	Animals ; Antigens, Surface/genetics ; Antigens, Surface/immunology ; Autoantibodies/immunology ; Blotting, Western ; Cells, Cultured ; Gene Expression Regulation ; Glomerular Filtration Rate ; Glomerulonephritis, Membranous/genetics ; Glomerulonephritis, Membranous/physiopathology ; Humans ; Kidney Glomerulus/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Membrane Proteins/metabolism ; Mice ; Podocytes/immunology ; Proteinuria/metabolism ; Sensitivity and Specificity ; Thrombospondins/immunology ; Thrombospondins/metabolism
Chemical Substances	Antigens, Surface ; Autoantibodies ; Membrane Proteins ; Thrombospondins ; Thsd7A protein, mouse
Language	English
Publishing date	2019-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2018090941
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3344: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage.

Sachs, Marlies / Wetzel, Sebastian / Reichelt, Julia / Sachs, Wiebke / Schebsdat, Lisa / Zielinski, Stephanie / Seipold, Lisa / Heintz, Lukas / Müller, Stephan A / Kretz, Oliver / Lindenmeyer, Maja / Wiech, Thorsten / Huber, Tobias B / Lüllmann-Rauch, Renate / Lichtenthaler, Stefan F / Saftig, Paul / Meyer-Schwesinger, Catherine

Journal of the American Society of Nephrology : JASN

2021 Volume 32, Issue 6, Page(s) 1389–1408

Abstract: Background: Podocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which ... ...

Abstract	Background: Podocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which could be mediated by shedding of cell-adhesion molecules through the regulated activity of cell surface-expressed proteases. A Disintegrin and Metalloproteinase 10 (ADAM10) is such a protease known to mediate ectodomain shedding of adhesion molecules, among others. Here we evaluate the involvement of ADAM10 in the process of antibody-induced podocyte injury. Methods: Membrane proteomics, immunoblotting, high-resolution microscopy, and immunogold electron microscopy were used to analyze human and murine podocyte ADAM10 expression in health and kidney injury. The functionality of ADAM10 ectodomain shedding for podocyte development and injury was analyzed, Results: ADAM10 is selectively localized at foot processes of murine podocytes and its expression is dispensable for podocyte development. Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner. Conclusions: ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.
MeSH term(s)	ADAM10 Protein/genetics ; ADAM10 Protein/metabolism ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Animals ; Autoantibodies/adverse effects ; Blood Urea Nitrogen ; Cadherins/metabolism ; Cell Adhesion ; Cell Communication ; Cell Membrane/metabolism ; Cells, Cultured ; Creatinine/urine ; Disease Models, Animal ; Female ; Glomerular Filtration Barrier/pathology ; Glomerular Filtration Barrier/physiopathology ; Humans ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis/metabolism ; Nephritis/pathology ; Nephrotic Syndrome/metabolism ; Nephrotic Syndrome/pathology ; Podocytes/metabolism ; Podocytes/pathology ; Podocytes/physiology ; Proteomics ; Renal Insufficiency, Chronic/metabolism ; Tissue Array Analysis ; Transcriptome ; Wnt Signaling Pathway
Chemical Substances	Autoantibodies ; Cadherins ; Membrane Proteins ; Creatinine (AYI8EX34EU) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; ADAM10 Protein (EC 3.4.24.81) ; ADAM10 protein, human (EC 3.4.24.81) ; Adam10 protein, mouse (EC 3.4.24.81)
Language	English
Publishing date	2021-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2020081213
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3344: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Tripartite Separation of Glomerular Cell Types and Proteomes from Reporter-Free Mice.

Hatje, Favian A / Wedekind, Uta / Sachs, Wiebke / Loreth, Desiree / Reichelt, Julia / Demir, Fatih / Kosub, Christopher / Heintz, Lukas / Tomas, Nicola M / Huber, Tobias B / Skuza, Sinah / Sachs, Marlies / Zielinski, Stephanie / Rinschen, Markus M / Meyer-Schwesinger, Catherine

Journal of the American Society of Nephrology : JASN

2021 Volume 32, Issue 9, Page(s) 2175–2193

Abstract: Background: The glomerulus comprises podocytes, mesangial cells, and endothelial cells, which jointly determine glomerular filtration. Understanding this intricate functional unit beyond the transcriptome requires bulk isolation of these cell types for ... ...

Abstract	Background: The glomerulus comprises podocytes, mesangial cells, and endothelial cells, which jointly determine glomerular filtration. Understanding this intricate functional unit beyond the transcriptome requires bulk isolation of these cell types for biochemical investigations. We developed a globally applicable tripartite isolation method for murine mesangial and endothelial cells and podocytes (timMEP). Methods: We separated glomerular cell types from wild-type or mT/mG mice Results: timMEP enabled protein-biochemical analyses of podocytes, mesangial cells, and endothelial cells derived from reporter-free mice, and allowed for the characterization of podocyte, endothelial, and mesangial proteomes of individual mice. We identified marker proteins for mesangial and endothelial proteins, and outlined protein-based, potential communication networks and phosphorylation patterns. The analysis detected cell type-specific proteome differences between mouse strains and alterations depending on sex, age, and transgene. After exposure to anti-THSD7A antibodies, timMEP resolved a fine-tuned initial stress response, chiefly in podocytes, that could not be detected by bulk glomerular analyses. The combination of proteomics with super-resolution imaging revealed a specific loss of slit diaphragm, but not of other foot process proteins, unraveling a protein-based mechanism of podocyte injury in this animal model. Conclusion: timMEP enables glomerular cell type-resolved investigations at the transcriptional and protein-biochemical level in health and disease, while avoiding reporter-based artifacts, paving the way toward the comprehensive and systematic characterization of glomerular cell biology.
MeSH term(s)	Animals ; Cell Separation/economics ; Cell Separation/methods ; Disease Models, Animal ; Female ; Glomerulonephritis, Membranous/etiology ; Glomerulonephritis, Membranous/metabolism ; Glomerulonephritis, Membranous/pathology ; Male ; Mesangial Cells ; Mice ; Mice, Inbred C57BL ; Podocytes ; Proteome
Chemical Substances	Proteome
Language	English
Publishing date	2021-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2020091346
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3344: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: The calcium-sensing receptor stabilizes podocyte function in proteinuric humans and mice.

Kidney international

2022 Volume 101, Issue 6, Page(s) 1186–1199

Abstract: Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria ... ...

Abstract	Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild-type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild-type littermates. Co-treatment of wild-type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild-type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease.
MeSH term(s)	Animals ; Calcium/metabolism ; Cinacalcet/pharmacology ; Cinacalcet/therapeutic use ; Doxorubicin/toxicity ; Humans ; Kidney Diseases/metabolism ; Mice ; Mice, Knockout ; Podocytes/metabolism ; Proteinuria/chemically induced ; Proteinuria/genetics ; Proteinuria/metabolism ; Receptors, Calcium-Sensing/genetics ; Receptors, Calcium-Sensing/metabolism
Chemical Substances	Receptors, Calcium-Sensing ; Doxorubicin (80168379AG) ; Calcium (SY7Q814VUP) ; Cinacalcet (UAZ6V7728S)
Language	English
Publishing date	2022-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2022.01.036
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 797: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks.

Reinicke, Anna T / Laban, Karoline / Sachs, Marlies / Kraus, Vanessa / Walden, Michael / Damme, Markus / Sachs, Wiebke / Reichelt, Julia / Schweizer, Michaela / Janiesch, Philipp Christoph / Duncan, Kent E / Saftig, Paul / Rinschen, Markus M / Morellini, Fabio / Meyer-Schwesinger, Catherine

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 16, Page(s) 7963–7972

Abstract: Ubiquitin C-terminal hydrolase L1 (UCH-L1) is one of the most abundant and enigmatic enzymes of the CNS. Based on existing UCH-L1 knockout models, UCH-L1 is thought to be required for the maintenance of axonal integrity, but not for neuronal development ... ...

Abstract	Ubiquitin C-terminal hydrolase L1 (UCH-L1) is one of the most abundant and enigmatic enzymes of the CNS. Based on existing UCH-L1 knockout models, UCH-L1 is thought to be required for the maintenance of axonal integrity, but not for neuronal development despite its high expression in neurons. Several lines of evidence suggest a role for UCH-L1 in mUB homeostasis, although the specific in vivo substrate remains elusive. Since the precise mechanisms underlying UCH-L1-deficient neurodegeneration remain unclear, we generated a transgenic mouse model of UCH-L1 deficiency. By performing biochemical and behavioral analyses we can show that UCH-L1 deficiency causes an acceleration of sensorimotor reflex development in the first postnatal week followed by a degeneration of motor function starting at periadolescence in the setting of normal cerebral mUB levels. In the first postnatal weeks, neuronal protein synthesis and proteasomal protein degradation are enhanced, with endoplasmic reticulum stress, and energy depletion, leading to proteasomal impairment and an accumulation of nondegraded ubiquitinated protein. Increased protein turnover is associated with enhanced mTORC1 activity restricted to the postnatal period in UCH-L1-deficient brains. Inhibition of mTORC1 with rapamycin decreases protein synthesis and ubiquitin accumulation in UCH-L1-deficient neurons. Strikingly, rapamycin treatment in the first 8 postnatal days ameliorates the neurological phenotype of UCH-L1-deficient mice up to 16 weeks, suggesting that early control of protein homeostasis is imperative for long-term neuronal survival. In summary, we identified a critical presymptomatic period during which UCH-L1-dependent enhanced protein synthesis results in neuronal strain and progressive loss of neuronal function.
MeSH term(s)	Animals ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/physiopathology ; Neurons/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Biosynthesis ; TOR Serine-Threonine Kinases/metabolism ; Ubiquitin Thiolesterase/deficiency ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/physiology
Chemical Substances	Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2019-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1812413116
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1148: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria.

Sachs, Wiebke / Sachs, Marlies / Krüger, Elke / Zielinski, Stephanie / Kretz, Oliver / Huber, Tobias B / Baranowsky, Anke / Westermann, Lena Marie / Voltolini Velho, Renata / Ludwig, Nataniel Floriano / Yorgan, Timur Alexander / Di Lorenzo, Giorgia / Kollmann, Katrin / Braulke, Thomas / Schwartz, Ida Vanessa / Schinke, Thorsten / Danyukova, Tatyana / Pohl, Sandra / Meyer-Schwesinger, Catherine

Journal of the American Society of Nephrology : JASN

2020 Volume 31, Issue 8, Page(s) 1796–1814

Abstract: Background: The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6- ... ...

Abstract	Background: The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms. Methods: MLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis. Results: Patients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis. Conclusions: Severe lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII.
MeSH term(s)	Albuminuria/etiology ; Animals ; Blood Urea Nitrogen ; Cells, Cultured ; Disease Models, Animal ; Humans ; Kidney Glomerulus/metabolism ; Lysosomes/metabolism ; Mice ; Mice, Inbred C57BL ; Mucolipidoses/complications ; Mucolipidoses/metabolism ; Proteasome Endopeptidase Complex/physiology ; Proteinuria/prevention & control ; Proteostasis/physiology
Chemical Substances	Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2020-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2019090960
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3344: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

To top

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito