Globoid cell leukodystrophy (GCL), or Krabbe disease, is a lysosomal storage disorder characterized by a deficiency in galactosylceramidase (GALC), which hydrolyses galactosylceramide and galactosylsphingosine (psychosine). Early detection of GCL in newborns is essential for timely therapeutic intervention and could be achieved by testing infant blood samples with isotopically labeled lysosmal enzyme substrates and mass spectrometry. While isotopically labeled psychosine would be a useful tool for the early diagnosis of GCL, its synthesis is lengthy and expensive. To obviate this problem we developed a one-step chemoenzymatic synthesis of psychosine using a glycosynthase mutant of the Rhodococcus equi endogalactosylceramidase (EGALC), α-D-galactopyranosyl fluoride and sphingosine.
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Ablation of lipocalin-2 reduces neuroinflammation in a mouse model of Krabbe disease.
Sci Rep
December 2024
Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14214, USA.
Lipocalin-2 (LCN2) is an acute-phase secretory molecule significantly upregulated in various neuroinflammatory and demyelinating conditions. Krabbe disease (KD) is a neurodegenerative lysosomal disorder caused by a galactosylceramidase (GALC) deficiency, accumulating cytotoxic psychosine in nervous systems, and subsequent neuroinflammation. Here, we show that LCN2 is highly overexpressed in GALC-deficient astrocytes.
View Article and Find Full Text PDFHuman iPSC-derived myelinating organoids and globoid cells to study Krabbe disease.
PLoS One
December 2024
Departments of Biochemistry and Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, United States of America.
Article Synopsis
- - Krabbe disease (Kd) is caused by a deficiency in the enzyme GALC, leading to the accumulation of the lipid galactosylceramide (GalCer), which produces a toxic lipid called psychosine that damages myelinating cells and leads to demyelination.
- - Research using induced pluripotent stem cells (iPSCs) from Kd patients revealed that Kd myelinating organoids exhibit early myelination defects without affecting other cell types, while the microglia in these organoids show changes in response to GalCer feeding.
- - The findings suggest that while Kd model organoids don't show classic lysosomal dysfunction, they provide an essential platform for studying the mechanisms behind demyel
Effects of Variants and Prenatal Exposition on the Glucosylsphingosine (Lyso-Gb1) Levels in Gaucher Disease Carriers.
Int J Mol Sci
November 2024
Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
Gaucher disease (GD) is a lysosomal lipid storage disorder caused by β-glucocerebrosidase (encoded by gene) activity deficiency, resulting in the accumulation of glucosylceramide (Gb1) and its deacylated metabolite glucosylsphingosine (lyso-Gb1). Lyso-Gb1 has been studied previously and proved to be a sensitive biomarker, distinguishing patients with GD from carriers and healthy subjects. It was shown that its level corresponds with β-glucocerebrosidase activity, thus it remains unknown as to why carriers have slightly higher lyso-Gb1 level than healthy population.
View Article and Find Full Text PDFMetabolic biomarkers of neonatal sepsis: identification using metabolomics combined with machine learning.
Front Cell Dev Biol
October 2024
Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Background: Sepsis is a common disease associated with neonatal and infant mortality, and for diagnosis, blood culture is currently the gold standard method, but it has a low positivity rate and requires more than 2 days to develop. Meanwhile, unfortunately, the specific biomarkers for the early and timely diagnosis of sepsis in infants and for the determination of the severity of this disease are lacking in clinical practice.
Methods: Samples from 18 sepsis infants with comorbidities, 25 sepsis infants without comorbidities, and 25 infants with noninfectious diseases were evaluated using a serum metabolomics approach based on liquid chromatography‒mass spectrometry (LC‒MS) technology.
Krabbe disease (KD) is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in the gene, which encodes for the enzyme galactosylceramidase (GALC). GALC is crucial for myelin metabolism. Functional deficiency of GALC leads to toxic accumulation of psychosine, dysfunction and death of oligodendrocytes, and eventual brain demyelination.
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