Johanna von Gerichten

Dr Johanna von Gerichten


Postdoctoral Research Fellow
Analytical Chemistry, Lipid Analysis, Lipidomics, Mass Spectrometry, GC or LC-MS(/MS)

My qualifications

2012
B.Sc. Biological Chemistry
University of Applied Sciences Mannheim, Germany
2014
M.Sc. Biomedical Science and Technology
University of Applied Sciences Mannheim, Germany

Previous roles

01 July 2014 - 31 July 2018
PhD student - Development of Mass Spectrometric Methods for Tissue Imaging and LC-based Quantification of Glycosphingolipids/Gangliosides including Tay-Sachs disease based Neuraminidase-deficient Mouse Models and Human Gut Microbiota -
German Cancer Research Center (DKFZ), Heidelberg, Germany

Academic networks

My publications

Publications

C Paget , S Deng, D Soulard, D Priestman, S Speca, J von Gerichten, A Speak, A Saroha, Y Pewzner-Jung, A Futerman, T Mallevaey, C Faveeuw, X Gu, F Platt , R Sandhoff, F Trottein (2019). TLR9-mediated dendritic cell activation uncovers mammalian ganglioside species with specific ceramide backbones that activate invariant natural killer T cells
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CD1d-restricted invariant natural killer T (iNKT) cells represent a heterogeneous population of lipid-reactive T cells that are involved in many immune responses, mediated through T-cell receptor (TCR)–dependent and/or independent activation. Although numerous microbial lipid antigens (Ags) have been identified, several lines of evidence have suggested the existence of relevant Ags of endogenous origin. However, the identification of their precise nature as well as the molecular mechanisms involved in their generation are still highly controversial and ill defined. Here, we identified two mammalian gangliosides—namely monosialoganglioside GM3 and disialoganglioside GD3—as endogenous activators for mouse iNKT cells. These glycosphingolipids are found in Toll-like receptor-stimulated dendritic cells (DC) as several species varying in their N-acyl fatty chain composition. Interestingly, their ability to activate iNKT cells is highly dependent on the ceramide backbone structure. Thus, both synthetic GM3 and GD3 comprising a d18:1-C24:1 ceramide backbone were able to activate iNKT cells in a CD1d-dependent manner. GM3 and GD3 are not directly recognized by the iNKT TCR and required the Ag presenting cell intracellular machinery to reveal their antigenicity. We propose a new concept in which iNKT cells can rapidly respond to pre-existing self-molecules after stress-induced structural changes in CD1d-expressing cells. Moreover, these gangliosides conferred partial protection in the context of bacterial infection. Thus, this report identified new biologically relevant lipid self-Ags for iNKT cells.
I Morace, R Pilz, G Federico, R Jennemann, D Krunic, V Nordström, J von Gerichten, C Marsching, I Schießl, J Müthing, C Wunder, L Johannes, R Sandhoff, H-J Gröne (2019). Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury
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To elucidate the physiologic function of renal globotriaosylceramide (Gb3/CD77), which up-to-date has been associated exclusively with Shiga toxin binding, we have analyzed renal function in Gb3-deficient mice. Gb3 synthase KO (Gb3S−/−) mice displayed an increased renal albumin and low molecular weight protein excretion compared to WT. Gb3 localized at the brush border and within vesicular structures in WT proximal tubules and has now been shown to be closely associated with the receptor complex megalin/cubilin and with albumin uptake. In two clinically relevant mouse models of acute kidney injury caused by myoglobin as seen in rhabdomyolysis and the aminoglycoside gentamicin, Gb3S−/− mice showed a preserved renal function and morphology, compared to WT. Pharmacologic inhibition of glucosylceramide-based glycosphingolipids, including Gb3, in WT mice corroborated the results of genetically Gb3-deficient mice. In conclusion, our data significantly advance the current knowledge on the physiologic and pathophysiologic role of Gb3 in proximal tubules, showing an involvement in the reabsorption of filtered albumin, myoglobin and the aminoglycoside gentamicin.
S Herzer, C Hagan, J von Gerichten, V Dieterle, B Munteanu, R Sandhoff, C Hopf and V Nordström (2018). Deletion of Specific Sphingolipids in Distinct Neurons Improves Spatial Memory in a Mouse Model of Alzheimer’s Disease
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Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and a concomitant loss of synapses and cognitive abilities. Recently, we have proposed that an alteration of neuronal membrane lipid microdomains increases neuronal resistance toward amyloid-β stress in cultured neurons and protects from neurodegeneration in a mouse model of AD. Lipid microdomains are highly enriched in a specific subclass of glycosphingolipids, termed gangliosides. The enzyme glucosylceramide synthase (GCS) catalyzes the rate-limiting step in the biosynthesis of these gangliosides. The present work now demonstrates that genetic GCS deletion in subsets of adult forebrain neurons significantly improves the spatial memory and counteracts the loss of dendritic spines in the hippocampal dentate gyrus of 5x familial AD mice (5xFAD//Ugcgf/f//Thy1-CreERT2//EYFP mice), when compared to 5xFAD//Ugcgf/f littermates (5xFAD mice). Aberrantly activated glial cells and their expression of pro-inflammatory cytokines have emerged as the major culprits for synaptic loss in AD. Typically, astrocytic activation is accompanied by a thickening of astrocytic processes, which impairs astrocytic support for neuronal synapses. In contrast to 5xFAD mice, 5xFAD//Ugcgf/f//Thy1-CreERT2//EYFP display a less pronounced thickening of astrocytic processes and a lower expression of tumor necrosis factor-α and interleukin 1-α in the hippocampus. Thus, this work further emphasizes that GCS inhibition may constitute a potential therapeutic target against AD.
V Seyrantepe, S A Demir, Z K Timur, J Von Gerichten, C Marsching, E Erdemli, E Oztas, K Takahashi, K Yamaguchi, N A Buket, D Demir, T Dalkara, K Erich, C Hopf, R Sandhoff, T Miyagi (2018). Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease
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Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal β-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexa/ mice have a normal lifespan and show no obvious neurological impairment until at least one year of age. These mice catabolize stored GM2 ganglioside using sialidase(s) to remove sialic acid and form the glycolipid GA2, which is further processed by β-hexosaminidase B. Therefore, the presence of the sialidase (s) allows the consequences of the Hexa defect to be bypassed. To determine if the sialidase NEU3 contributes to GM2 ganglioside degradation, we generated a mouse model with combined deficiencies of HEXA and NEU3. The Hexa/ Neu3/ mice were healthy at birth, but died at 1.5 to 4.5 months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexa/ Neu3/ mice revealed the abnormal accumulation of GM2 ganglioside. Histological and immunohistochemical analysis demonstrated cytoplasmic vacuolation in the neurons. Electron microscopic examination of the brain, kidneys and testes revealed pleomorphic inclusions of many small vesicles and complex lamellar structures. The Hexa/ Neu3/ mice exhibited progressive neurodegeneration with neuronal loss, Purkinje celldepletion, and astrogliosis. Slow movement, ataxia, and tremors were the prominent neurological abnormalities observed in these mice. Furthermore, radiographs revealed abnormalities in the skeletal bones of the Hexa/ Neu3/ mice. Thus, the Hexa/ Neu3/ mice mimic the neuropathological and clinical abnormalities of the classical early-onset Tay-Sachs patients, and provide a suitable model for the future pre-clinical testing of potential treatments for this condition.
J von Gerichten, K Schlosser, D Lamprecht, I Morace, M Eckhardt, D Wachten, R Jennemann, H-J Gröne, M Mack, and R Sandhoff (2017). Diastereomer-specific quantification of bioactive hexosylceramides from bacteria and mammals
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Mammals synthesize, cell-type specifically, the diastereomeric hexosylceramides, -galactosylceramide (GalCer) and -glucosylceramide (GlcCer), which are involved in several diseases, such as sphingolipidosis, diabetes, chronic kidney diseases, or cancer. In contrast, Bacteroides fragilis, a member of the human gut microbiome, and the marine sponge, Agelas mauritianus, produce -GalCer, one of the most potent stimulators for invariant natural killer T cells. To dissect the contribution of these individual stereoisomers to pathologies, we established a novel hydrophilic interaction chromatography-based LC-MS2 method and separated (R > 1.5) corresponding diastereomers from each other, independent of their lipid anchors. Testing various bacterial and mammalian samples, we could separate, identify (including the lipid anchor composition), and quantify endogenous -GlcCer, -GalCer, and -GalCer isomers without additional derivatization steps. Thereby, we show a selective decrease of -GlcCers versus -GalCers in cell-specific models of GlcCer synthase-deficiency and an increase of specific -GlcCers due to loss of -glucoceramidase 2 activity. Vice versa, -GalCer increased specifically when cerebroside sulfotransferase (Gal3st1) was deleted. We further confirm -GalCer as substrate of globotriaosylceramide synthase for galabiaosylceramide synthesis and identify additional members of the human gut microbiome to contain immunogenic -GalCers. Finally, this method is shown to separate corresponding hexosylsphingosine standards, promoting its applicability in further investigations
A Fülöp, D S, K Erich, J von Gerichten, P van Hoogevest, R Sandhoff & C Hopf (2016). Molecular imaging of brain localization of liposomes in mice using MALDI mass spectrometry
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Phospholipids have excellent biocompatibility and are therefore often used as main components of liposomal drug carriers. In traditional bioanalytics, the in-vivo distribution of liposomal drug carriers is assessed using radiolabeled liposomal constituents. This study presents matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as an alternative, label-free method for ex-vivo molecular imaging of liposomal drug carriers in mouse tissue. To this end, indocyanine green as cargo and two liposomal markers, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated with monodisperse polyethylene glycol (PEG36-DSPE) were incorporated into liposomal carriers and administered to mice. We used MALDI MSI of the two lipid markers in both positive and negative ion mode for visualization of liposome integrity and distribution in mouse organs. Additional MSI of hemoglobin in the same tissue slice and pixel-by-pixel computational analysis of co-occurrence of lipid markers and hemoglobin served as indicator of liposome localization either in parenchyma or in blood vessels. Our proof-of-concept study suggests that liposomal components and indocyanine green distributed into all investigated organs.