Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reduction <i>in vitro</i>

Brogden, Graham; Shammas, Hadeel; Maalouf, Katia; Naim, Samara L.; Wetzel, Gabi; Amiri, Mahdi; Köckritz-Blickwede, Maren von; Naim, Hassan Y.

doi:10.1042/bsr20160402

Cited by 17 publications

(21 citation statements)

References 33 publications

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“…In fact, it is already known that lysosomal storage disorders may impair membrane trafficking. 37,38 All of these hypotheses need to be verified by further histological or ultrastructural studies of the eyes from patients with this rare disorder.…”

Section: Discussionmentioning

confidence: 99%

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography

Minnella

Barbano

Verrecchia

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Fabry disease (FD) is a multiorgan X-linked condition characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in a progressive intralysosomal deposit of globotriaosylceramide. The aim of this study was to evaluate the macular ultrastructure of the vascular network using optical coherence tomography angiography (OCTA) and to evaluate macular function using focal electroretinography (fERG) in Fabry patients (FPs). METHODS. A total of 20 FPs (38 eyes, mean age 57 6 2.12 SD, range of 27-80 years) and 17 healthy controls (27 eyes, mean age 45 years 6 20.50 SD, range of 24-65 years) were enrolled in the study. Color fundus photography, swept-source optical coherence tomography (SS-OCT), OCTA and fERG were performed in all subjects. The OCTA foveal avascular zone (FAZ), vasculature structure, superficial and deep retinal plexus densities (images of 4.5 3 4.5 mm) and fERG amplitudes were measured. Group differences were statistically assessed by Student's t-test and ANOVA. RESULTS. In the FP group, the FAZ areas of the superficial and deep plexuses were enlarged (P ¼ 0.036, t ¼ 2.138; P < 0.001, t ¼ À3.889, respectively), the vessel density was increased in the superficial plexus, and the fERG amplitude was reduced (P < 0.001, t ¼ À10.647) compared with those in healthy controls. No significant correlations were found between the structural and functional data. CONCLUSIONS. OCTA vascular abnormalities and reduced fERG amplitudes indicate subclinical signs of microangiopathy with early retinal dysfunction in FPs. This study highlights the relevance of OCTA imaging analysis in the identification of abnormal macular vasculature as an ocular hallmark of FD.

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Section: Discussionmentioning

confidence: 99%

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography

Minnella

Barbano

Verrecchia

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Lipid rafts were isolated from fibroblasts as described previously [85]. All solutions, materials, and handling were performed at 0-4 • C. After two washes with phosphate buffered saline, pH 7.4 (PBS), cells were scraped into 500 µL raft buffer (1% Triton X 100 in PBS) containing protease inhibitors.…”

Section: Lipid Raft Isolation and Western Blottingmentioning

confidence: 99%

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

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“…Total lipids from the sucrose gradient fractions were extracted by the method of Bligh and Dyer [40] with slight modifications, as described previously [41]. Cholesterol analysis was performed with a Hitachi Chromaster HPLC, as described by Brogden et al [42,43].…”

Section: Lipid Extraction and Lipid Composition Analysismentioning

confidence: 99%

Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line

Toutounji¹,

Wanes²,

El-Harakeh

et al. 2020

IJMS

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A key morphological feature of inflammatory bowel disease (IBD) is the loss of the barrier function of intestinal epithelial cells. The present study investigates endoplasmic reticulum (ER) stress in addition to alterations in protein and membrane trafficking in a dextran sulfate sodium (DSS)-induced IBD-like phenotype of intestinal Caco-2 cells in culture. DSS treatment significantly reduced the transepithelial electric resistance (TEER) and increased the epithelial permeability of Caco-2 cells, without affecting their viability. This was associated with an alteration in the expression levels of inflammatory factors in addition to an increase in the expression of the ER stress protein markers, namely immunoglobulin-binding protein (BiP), C/EBP homologous protein (CHOP), activation transcription factor 4 (ATF4), and X-box binding protein (XBP1). The DSS-induced ER-stress resulted in impaired intracellular trafficking and polarized sorting of sucrase-isomaltase (SI) and dipeptidyl peptidase-4 (DPPIV), which are normally sorted to the apical membrane via association with lipid rafts. The observed impaired sorting was caused by reduced cholesterol levels and subsequent distortion of the lipid rafts. The data presented confirm perturbation of ER homeostasis in DSS-treated Caco-2 cells, accompanied by impairment of membrane and protein trafficking resulting in altered membrane integrity, cellular polarity, and hence disrupted barrier function.

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Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reduction in vitro

Cited by 17 publications

References 33 publications

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line

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