Gaucher disease: Chemotactic factors and immunological cell invasion in a mouse model

Pandey, Manoj Kumar; Jabre, Nicholas A.; Xu, You-Hai; Zhang, Wujuan; Setchell, Kenneth D.R.; Grabowski, Gregory A.

doi:10.1016/j.ymgme.2013.09.002

Cited by 32 publications

(28 citation statements)

References 45 publications

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“…Macrophages, DCs, PMNs, and T cells from these mice showed excess GC as a potential basis for activation of Th1 (IFN-␥, IL-12, TNF-␣) and Th17 (IL-17A/F) cytokine production (94,134,138). Increased level of chemokines, the corresponding monocytes, DCs, PMNs, T cells, and B cells were also identified in these mice, which may underlie the pathological trafficking of immune cells to sites of inflammation in GD (83,133,137). Enhanced chemotaxis of bone marrow-derived macrophages, DC, and T and B lymphocytes was found in the lung, spleen, and liver (83,133,137).…”

Section: Patients With Gaucher's Disease Before and After Enzyme Replmentioning

confidence: 84%

“…Increased level of chemokines, the corresponding monocytes, DCs, PMNs, T cells, and B cells were also identified in these mice, which may underlie the pathological trafficking of immune cells to sites of inflammation in GD (83,133,137). Enhanced chemotaxis of bone marrow-derived macrophages, DC, and T and B lymphocytes was found in the lung, spleen, and liver (83,133,137).…”

Section: Patients With Gaucher's Disease Before and After Enzyme Replmentioning

confidence: 89%

“…GM3 impairs glucose uptake via suppression of insulin-stimulated tyrosine phosphorylation of the insulin receptor (125,166,170). GM3 displaces the insulin receptor in lipid rafts, decreasing insulin receptor-dependent signaling (126,129,133).…”

Section: Alteration Of Insulin Sensitivity In Patients With Gdmentioning

confidence: 99%

“…HDL-c levels are abnormally low in type I GD. However, the low HDL-c levels do not lead to premature atherosclerosis, as assessed by carotid artery intima-media thickness measurement in GD (40,42,133). Leptin is strongly associated with insulin and the HOMA index and was suggested as a biomarker to assess early evidence of insulin resistance in patients with GD (45, 47, 132).…”

Section: Alteration Of Insulin Sensitivity In Patients With Gdmentioning

confidence: 99%

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Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Ilan

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.

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Section: Patients With Gaucher's Disease Before and After Enzyme Replmentioning

confidence: 84%

Section: Patients With Gaucher's Disease Before and After Enzyme Replmentioning

confidence: 89%

Section: Alteration Of Insulin Sensitivity In Patients With Gdmentioning

confidence: 99%

Section: Alteration Of Insulin Sensitivity In Patients With Gdmentioning

confidence: 99%

See 2 more Smart Citations

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Ilan

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Neutrophilia is also observed in the Gaucher mouse, with a hypothesized etiology of intracellular storage in antigen presenting cells and release of granulocyte colony stimulating factors to mobilize hematopoietic progenitor cells. Additionally, neutrophil recruiting chemokines CXCL-1 and -2 were also detected in sera from Gaucher mice [62]. Levels of CXCL and granulocyte colony stimulating factors have not been measured in SD cats but could further elucidate the cause of neutrophilia.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

Bradbury

Gray‐Edwards

Shirley

et al. 2015

Experimental Neurology

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The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated GM2 patients and those in future clinical trials.

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Identification of a novel therapeutic target underlying atypical manifestation of Gaucher disease

Kim

Jeong

et al. 2022

Clinical & Translational Med

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Dear Editor,In the present study, we delineate the molecular pathways underlying atypical progressions of Gaucher disease (GD) that lead to unresponsiveness to enzyme replacement therapy (ERT). Specifically, we observed the accumulation of dense substrates (e.g., glucosylsphingosine [Lyso-Gb1]), which was associated with alterations in complement activity, autophagy metabolism, macrophage polarization and TGF-β signaling and subsequent endothelialto-mesenchymal transition (EndMT) and fibrosis. We also describe the potential therapeutic role of ambroxol, a chemical chaperone in GD, and highlight the need for a multi-functional therapeutic approach in managing GD cases with atypical progression.GD is caused by the deficiency of glucocerebrosidase (GCase) encoded by the glucocerebrosidase1 gene, which leads to the accumulation of glucosylceramide and Lyso-Gb1 in the lysosome. Specifically, Lyso-Gb1 plays important pathogenic roles in GD such as inflammation, impairment of cytoplasmic division, alteration of immune regulation and neurotoxicity. 1-3 GD can be categorized according to the degree of neurologic involvement: non-neuropathic (GD1), acute neuronopathic (GD2) and chronic neuronopathic (GD3). Since the advent of ERT, the clinical outcomes of patients with GD have improved remarkably; however, despite ERT, most GD2/3 patients as well as some GD1 patients show atypical manifestations such as lymphadenopathy, multiple myeloma, lymphoma, neurological deterioration and increases in Lyso-Gb1 levels. 4 The molecular mechanism underlying atypical responses to ERT is poorly understood.We evaluated the histological features of lymph nodes from three patients with GD, including submandibular lymph node from Pt1 (GD1, G85E/F252I), stomach lymph node from Pt2 (GD1, R87W/R296Q) and mesenteric lymph node from Pt3 (GD3, L483P/L483P) (Table S1). Despite 5 years of ERT, Pt3 died from progressiveThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Gaucher disease: Chemotactic factors and immunological cell invasion in a mouse model

Cited by 32 publications

References 45 publications

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

Identification of a novel therapeutic target underlying atypical manifestation of Gaucher disease

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