Markedly perturbed hematopoiesis in acid ceramidase deficient mice

Dworski, Shaalee; Berger, Alexandra; Furlonger, Caren; Moreau, Joshua M.; Yoshimitsu, Makoto; Trentadue, Jessa; Au, Bryan; Paige, Christopher J.; Medin, Jeffrey A.

doi:10.3324/haematol.2014.108530

Cited by 18 publications

(20 citation statements)

References 14 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings indicate a severe defect in T cell maturation in our Farber model. A similar phenotype was also described for the point mutation model (Dworski et al, 2015). Dworski and colleagues also showed that this T cell maturation defect aggravates with time and coincides with foam cell infiltration in immune organs, suggesting that the foam cells disrupt the niche for the development of these cells (Dworski et al, 2017).…”

Section: Discussionsupporting

confidence: 60%

Pathological manifestations of Farber disease in a new mouse model

Beckmann

Kadow

Schumacher

et al. 2018

Biological Chemistry

View full text Add to dashboard Cite

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.

show abstract

Section: Discussionsupporting

confidence: 60%

Pathological manifestations of Farber disease in a new mouse model

Beckmann

Kadow

Schumacher

et al. 2018

Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Mice with a Farber-like disease are characterized by significantly increased circulating monocytes and neutrophils and decreased T cells compared to normal controls (20). The hematological abnormalities in 60-d-old Twi/FD mice were similar to those observed in age-matched FD mice with larger circulating monocyte (Ly6G − Ly6C hi ) and neutrophil (Ly6G + Ly6C + ) populations and significantly smaller T cell (CD3 + ) populations compared to WT mice (SI Appendix, Fig.…”

Section: Resultssupporting

confidence: 53%

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Benitez

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing “psychosine hypothesis.” We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.

show abstract

“…An increased prevalence of inflammatory cells has been previously reported in the lungs, brain, and hematopoietic organs in this mouse model of FD. 21,22,32 Thus, finding that a deficiency in ACDase activity also leads to inflammation in the eye and optic nerve could be expected. Through the use of noninvasive ocular imaging, the formation of granulomas and nodules was noted in the anterior chambers.…”

Section: Discussionmentioning

confidence: 98%

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Sajdak

Sikora

et al. 2019

The American Journal of Pathology

View full text Add to dashboard Cite

Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1 P361R/P361R mice. Asah1 P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1 P361R/ P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment. (Am J Pathol 2019, 189: 320e338; https://doi.

show abstract

Markedly perturbed hematopoiesis in acid ceramidase deficient mice

Cited by 18 publications

References 14 publications

Pathological manifestations of Farber disease in a new mouse model

Pathological manifestations of Farber disease in a new mouse model

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Contact Info

Product

Resources

About