No abstract

Cystic fibrosis (CF), one of the most common lethal hereditary diseases of white European populations, is caused by loss-of-function mutations in the CF Transmembrane conductance Regulator (CFTR) gene. One of the main causes of mortality is the onset of CF lung disease, which is characterized by chronic infection and inflammation resulting in the progressive remodelling, irreversible damage and fibrosis of the airways. An increasing number of studies indicate that sphingolipids are crucial players in pulmonary manifestations of CF, even if their direct involvement in CF lung disease is still unclear. In this review, we give an overview of the role of sphingolipids in CF pulmonary disease, focusing on the relationship between glycosphingolipids and lung inflammation, which represents the main hallmark of this disease.

ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A4G (r.124a4g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.

Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose-loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids ( i.e., sphingomyelin, glucosylceramide, ceramide, and the gangliosides GM3 and GD3), at both intracellular and plasma membrane (PM) levels. In addition, we observed an increase in the lysosomal membrane protein Lamp-1 on the PM of sucrose-loaded fibroblasts and a greater release of the soluble lysosomal protein cathepsin D in their extracellular medium compared with controls. These results indicate increased fusion between lysosomes and the PM, as also suggested by the increased activity of lysosomal glycosphingolipid hydrolases on the PM of sucrose-loaded fibroblasts. The inhibition of β-glucocerebrosidase and nonlysosomal glucosylceramidase, both involved in ceramide production resulting from glycosphingolipid catabolism on the PM, partially restored cell proliferation. Our findings indicate the existence of a new molecular mechanism underlying cell damage triggered by lysosomal impairment.-Samarani, M., Loberto, N., Soldà, G., Straniero, L., Asselta, R., Duga, S., Lunghi, G., Zucca, F. A., Mauri, L., Ciampa, M. G., Schiumarini, D., Bassi, R., Giussani, P., Chiricozzi, E., Prinetti, A., Aureli, M., Sonnino, S. A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest.

Sphingolipids (SLs) are amphiphilic molecules mainly associated with the external leaflet of eukaryotic plasma membrane, and are structural membrane components with key signaling properties. Since the beginning of the last century, a large number of papers described the involvement of these molecules in several aspects of cell physiology and pathology. Several lines of evidence support the critical role of SLs in inflammatory diseases, by acting as anti- or pro-inflammatory mediators. They are involved in control of leukocyte activation and migration, and are recognized as essential players in host response to pathogenic infection. We propose here a critical overview of current knowledge on involvement of different classes of SLs in inflammation, focusing on the role of simple and complex SLs in pathogen-mediated inflammatory response.