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

Abstract

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.

Verteporfin treatment controls morphology, phenotype, and global gene expression for cells of the human nucleus pulposus

“…transport. [64][65][66][67][68][69][70][71][72][73] Examining themes in the gene sets over time reveals the most enriched gene sets in the downregulated genes at 24 hours were largely related to the membrane, but by 48 hours the top gene sets were related to extracellular components and cellular interaction with ECM proteins (Data S4). Interestingly, at 4 days the top enriched gene sets among downregulated genes were related to a mix of organelle lumens, extracellular organization, and metabolism ( Figure 5 and Data S4).…”

Sphingolipids as Emerging Mediators in Retina Degeneration

“…Intra-vitreal C2-Cer injection causes vision loss in rats, increasing apoptosis and expression of glial fibrillary acidic protein, a marker of gliosis (Lou et al, 2017). A recent work in a mouse model of Farber disease, with a deficiency in acid ceramidase activity, provides direct evidence of accumulation of Cer in the retina, associated to inflammation and severe visual loss (Yu et al, 2018). Ischemia increases the expression of acid SMase, increasing Cer levels and leading to retinal degeneration in wild type mice; reduction of this expression in an acid SMase +/- mouse model decreases Cer levels, protects retina structure and preserves its function after ischemic injury (Fan et al, 2016).…”

Downregulation of Lysosomal Acid Ceramidase Mediates HMGB1-Induced Migration and Proliferation of Mouse Coronary Arterial Myocytes

“…It is known that ceramide can be hydrolyzed by AC to form both sphingosine and a free fatty acid; in addition, a deficiency of AC leads to an accumulation of ceramide (Yu et al, 2018b(Yu et al, , 2019. Based on this knowledge, we quantified ceramide levels in CAMs by liquid chromatography-tandem mass spectrometry (LC-MS/MS).…”