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Deep phenotyping of SH-Sy5y cells exposed to glucosylsphingosine by LC-MS

ABSTRACT: SH-Sy5y cells were exposed to glucosylsphingosine (GlcSph) at two concentrations observed in moderate (20 ng/mL) and severe (200 ng/mL) Gaucher disease phenotypes and subjected to label free proteomics to identify cellular pathways and molecules affected by GlcSph. Lyso-Gb3, a lipid accumulating in Fabry disease, which exhibits no nerodegeneration, was used as a disease control. DMSO was used as a vehicle control.Proteomics analysis demonstrated a negative effect of GlcSph on cell metabolism, particularly affecting the TCA cycle, mitochondrial function, glycolysis and protein ubiquitination.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Valeria Nikolaenko

LAB HEAD: Wendy Heywood

PROVIDER: PXD061666 | Pride | 2025-09-01

REPOSITORIES: Pride

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			Action	DRS
	20190907_Fr1_Ctrl_rep_1.raw.tar	Raw
	20190907_Fr1_Ctrl_rep_2.raw.tar	Raw
	20190907_Fr1_GlcSph_200_rep_1.raw.tar	Raw
	20190907_Fr1_GlcSph_200_rep_2.raw.tar	Raw
	20190907_Fr1_GlcSph_20_rep_1.raw.tar	Raw

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Publications

Glucosylsphingosine affects mitochondrial function in a neuronal cell model.

Nikolaenko Valeria V Vootukuri Reddy R Eaton Simon S Hällqvist Jenny J Baldwin Tomas T Mills Kevin K Heywood Wendy W

Communications biology 20250821 1

Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson's disease. Glucosylsphingosine is a biomarker for Gaucher disease and studies demonstrate its relevance to disease pathology, yet the mechanisms of its toxicity remain little understood. Using proteomics, we show that incubation of SH-Sy5y cells with glucosyls ...[more]

PMID: 40841705

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Project description:Recent studies in non-human model systems have shown therapeutic potential of modified mRNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the ÃŽÂ±-galactosidase (GLA) gene in a human cardiac model generated from induced-pluripotent stem cell-derived from two patients with Fabry disease. In line with the clinical phenotype, cardiomyocytes from Fabry patientÃ¢â‚¬â„¢s induced pluripotent stem cells show accumulation of the glycosphinolipid Globotriaosylceramide (GB3), which is an ÃŽÂ±-galactosidase substrate. Further, the patient-specific cardiomyocytes have significant upregulation of lysosomal associated proteins. Upon modRNA treatment, a subset of lysosomal proteins were partially restored to wildtype levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA treated cardiomyocytes demonstrating that ÃŽÂ±-galactosidase enzymatic activity was restored. Together, our results validate the utility of patient IPSC-derived cardiomyocytes as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.

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Project description:Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement (ERT) or chaperone mediated stabilization, thereby alleviating lysosome dysfunction. However, the therapeutic effect in the regression of end-organ damage (ie. kidney damage) is limited. Ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not alter podocyte injury. A novel CRISPR-/CAS9-mediated -Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptomic-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury.

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Delivery of A4GALT targeting siRNA-lipid nanoparticle rescues fabry disease phenotypes in hiPSC derived endothelial cell and podocyte models

Project description:In this study, we explore the therapeutic feasibility of globotriaosylceramide (Gb3) synthase (A4GALT)-specific siRNA-loaded polyhistidine (pHis)-incorporated lipid nanoparticles (HLNPs) for Fabry disease (FD). HLNPs were developed to deliver siRNAs targeting A4GALT using a microfluidic device, with pHis aiding in endosome escape. The therapy was tested on GLA-knockout human induced pluripotent stem cell-derived endothelial cells (GLA-KO-hiPSC-ECs) and podocytes (GLA-KO-hiPSC-PCs). GLA-KO-hiPSCs-ECs or -PCs, upon differentiation, were treated with A4GALT-siRNA-HLNP. Successful intracellular uptake of A4GALT-siRNA-HLNP was confirmed through fluorescence and electron microscopy in both cell types. A4GALT-siRNA-HLNP treatment confirmed both cell types' stability at 5 µg/mL. Increased Gb3 deposition and zebra body formation were detected in both cell types, but A4GALT-siRNA-HLNP treatment attenuated these FD phenotypes, demonstrating reduced expression of A4GALT through western blot analysis. RNA sequencing analysis revealed that the expression of transcripts associated with FD in both cell types was restored by A4GALT-siRNA-HLNP treatment. Suppression of A4GALT via siRNA/HLNP treatment significantly rescued FD phenotypes, presenting a novel therapeutic approach for FD.

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Mitochondrial stress in GLA mutants Zebrafish is independent of globotriaosylceramide accumulation

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