Altered level of plasma exosomes in patients with Gaucher disease

Shtam, Tatiana; Naryzhny, Stanislav N.; Kulabukhova, D. G.; Luiza, Garaeva; Senkevich, Konstantin; Landa, Sergey; Varfolomeeva, E. Yu.; Salogub, Galina; Верлов, Н. А.; Arthur, Kopylov; Elena, Zorina; Kamyshinsky, Roman; Usenko, Tatiana; Alexander, Schwarzman; Zakharova, Ekaterina; Anton, Emil; Pchelina, Sofya

doi:10.1016/j.ejmg.2020.104038

Cited by 13 publications

(14 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, our characterization of the number of EVs, protein content and size showed consistent similarities between EVs from both genotypes. It is important to note that in other LSDs such as Gaucher disease, differences in EV size were reported in plasma [ 39 ]. However, while small, non-significant, differences were observed in EV sizes between MLD and age matched control mice, these changes seem not to be disease related.…”

Section: Discussionmentioning

confidence: 99%

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice

et al. 2022

View full text Add to dashboard Cite

Background Recent findings show that extracellular vesicle constituents can exert short- and long-range biological effects on neighboring cells in the brain, opening an exciting avenue for investigation in the field of neurodegenerative diseases. Although it is well documented that extracellular vesicles contain many lipids and are enriched in sphingomyelin, cholesterol, phosphatidylserines and phosphatidylinositols, no reports have addressed the lipidomic profile of brain derived EVs in the context of Metachromatic Leukodystrophy, a lysosomal storage disease with established metabolic alterations in sulfatides. Methods In this study, we isolated and characterized the lipid content of brain-derived EVs using the arylsulfatase A knockout mouse as a model of the human condition. Results Our results suggest that biogenesis of brain-derived EVs is a tightly regulated process in terms of size and protein concentration during postnatal life. Our lipidomic analysis demonstrated that sulfatides and their precursors (ceramides) as well as other lipids including fatty acids are altered in an age-dependent manner in EVs isolated from the brain of the knockout mouse. Conclusions In addition to the possible involvement of EVs in the pathology of Metachromatic Leukodystrophy, our study underlines that measuring lipid signatures in EVs may be useful as biomarkers of disease, with potential application to other genetic lipidoses.

show abstract

Section: Discussionmentioning

confidence: 99%

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Further improvements in GD screening protocols may be possible through the use of more comprehensive electronic health records and by the addition of other biomarkers such as exosome size or heat shock protein 70 (HSP70) on fluorescent cell sorting profiles 28 …”

Section: Discussionmentioning

confidence: 99%

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study

et al. 2021

View full text Add to dashboard Cite

Aims Lysosomal β‐glucocerebrosidase A (GBA) deficiency causes Gaucher disease (GD), a recessive disorder caused by bi‐allelic mutations in GBA. The prevalence of GD is associated with ethnicity but largely unknown and potentially underestimated in many countries. GD may manifest with organomegaly, bone involvement, and neurological symptoms as well as abnormal laboratory biomarkers. This study attempted to screen for GD in patients using abnormal platelet, alkaline phosphatase (ALP), and ferritin results from laboratory databases. Methods Electronic laboratory databases were interrogated using a 2‐ to 4‐year time interval to identify from clinical biochemistry records patients with a phenotype of reduced platelets (<150 × 109/L) and either elevated ALP (>130 iu/L) or ferritin [>150 (female) or >250 µg/L (male)]. The mean value over the screening window was used to reduce variability in results. A dried blood spot sample was collected for the determination of GBA activity in patients meeting these criteria. If low GBA activity was found, then the concentration of the GD‐specific biomarker glucosyl‐sphingosine (lyso‐GB1) was assayed, and the GBA gene sequenced. Results Samples were obtained from 1058 patients; 232 patients had low GBA activity triggering further analysis. No new cases of GD with homozygosity for pathogenic variants were identified, but 12 patients (1%) were identified to be carriers of a pathogenic variant in GBA. Conclusions Pathology databases hold routine information that can be used to screen for patients with inherited errors of metabolism. However, biochemical screening using mean platelets, ALP, and ferritin has a low yield for unidentified cases of GD.

show abstract

“…Likewise, exosomes have gained increased attention since they participate in cellular communication and signaling in a bidirectional way in health and disease. Interestingly, plasma from GD patients presents large and multilayered exosomes with various morphologies compared to healthy controls (Tatiana et al, 2020 ). Some of these exosomes were electron-dense and had a higher fluorescence intensity of exosome markers CD9 and CD81 than controls (Tatiana et al, 2020 ).…”

Section: Dysregulation Of Organelles In Ngdmentioning

confidence: 99%

“…Interestingly, plasma from GD patients presents large and multilayered exosomes with various morphologies compared to healthy controls (Tatiana et al, 2020 ). Some of these exosomes were electron-dense and had a higher fluorescence intensity of exosome markers CD9 and CD81 than controls (Tatiana et al, 2020 ). In this regard, Papadopoulos et al showed that β-GC inhibition increases the number of brain exosomes and α-syn-associated exosomes in an overexpressing α-syn mouse model treated with CβE.…”

Section: Dysregulation Of Organelles In Ngdmentioning

confidence: 99%

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

Arévalo

Lamaizon²,

Cavieres³

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Gaucher disease (GD) is an inherited disorder caused by recessive mutations in the GBA1 gene that encodes the lysosomal enzyme β-glucocerebrosidase (β-GC). β-GC hydrolyzes glucosylceramide (GluCer) into glucose and ceramide in the lysosome, and the loss of its activity leads to GluCer accumulation in different tissues. In severe cases, enzymatic deficiency triggers inflammation, organomegaly, bone disease, and neurodegeneration. Neuronopathic Gaucher disease (nGD) encompasses two different forms of the disease, characterized by chronic or acute damage to the central nervous system (CNS). The cellular and molecular studies that uncover the pathological mechanisms of nGD mainly focus on lysosomal dysfunction since the lysosome is the key organelle affected in GD. However, new studies show alterations in other organelles that contribute to nGD pathology. For instance, abnormal accumulation of GluCer in lysosomes due to the loss of β-GC activity leads to excessive calcium release from the endoplasmic reticulum (ER), activating the ER-associated degradation pathway and the unfolded protein response. Recent evidence indicates mitophagy is altered in nGD, resulting in the accumulation of dysfunctional mitochondria, a critical factor in disease progression. Additionally, nGD patients present alterations in mitochondrial morphology, membrane potential, ATP production, and increased reactive oxygen species (ROS) levels. Little is known about potential dysfunction in other organelles of the secretory pathway, such as the Golgi apparatus and exosomes. This review focuses on collecting evidence regarding organelle dysfunction beyond lysosomes in nGD. We briefly describe cellular and animal models and signaling pathways relevant to uncovering the pathological mechanisms and new therapeutic targets in GD.

show abstract

Altered level of plasma exosomes in patients with Gaucher disease

Cited by 13 publications

References 38 publications

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

Contact Info

Product

Resources

About