Elevation of lung surfactant phosphatidylcholine in mouse models of Sandhoff and of Niemann–Pick A disease

Abstract

Sandhoff disease is caused by the defective activity of the lysosomal enzyme beta-hexosaminidase, resulting in accumulation of the glycolipids, GA2 and GM2. Niemann-Pick A/B disease is caused by the defective activity of lysosomal acid sphingomyelinase resulting in sphingomyelin accumulation. Pulmonary complications have been observed in both diseases. We now demonstrate changes in phospholipid levels in pulmonary surfactant in mouse models of these diseases. In the Hexb mouse, a model of Sandhoff disease, lipid phosphate levels were elevated in surfactant from 3- and 4-month-old mice, which was mainly due to elevated levels of phosphatidylcholine. In the ASM mouse, a model of Niemann-Pick A disease, levels of the primary storage material, sphingomyelin, were elevated as expected, and levels of phosphatidylcholine and two other phospholipids were also significantly elevated in pulmonary surfactant and in lung tissue from 5-, 6- and 7-month-old mice. These results suggest that changes in phospholipid levels and composition in lung surfactant might be a general feature of sphingolipid storage diseases, which may be in part responsible for the increased susceptibility of these patients to respiratory infections and lung pathology, often the main reason for the death of these patients.

Mutation of Serine 32 to Threonine in Peroxiredoxin 6 Preserves Its Structure and Enzymatic Function but Abolishes Its Trafficking to Lamellar Bodies

“…Changes in phospholipid content represent a hallmark for lysosomal storage disorders that result from the deficiency of LB hydrolases, and increased lung phospholipid content of 4 -6-fold has been reported in lungs of patients affected by sialidosis and Gaucher and Sandhoff diseases (51). A similar increase in lung phospholipids has been found in mouse models of these diseases as, for example, the ␤-hexosaminidase-deficient mouse (50).…”

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

“…Sphingolipids, in particular sphingomyelin, were recently shown to be a component of pulmonary surfactant [83]. Whether the alterations of pulmonary ceramide also affect surfactant in cystic fibrosis patients is presently unknown.…”

Hydrolysis of phosphatidylcholine by cerium(IV) releases significant amounts of choline and inorganic phosphate at lysosomal pH

“…A major complication in common to the inherited, metabolic lysosomal storage disorders Niemann-Pick disease types A and B, Sandhoff disease, and Gaucher disease type I is compromised pulmonary function [3][4][5][6][7][8][9][10][11][12]. Bronchoalveolar lavage fluid collected from Sandhoff disease, and Gaucher disease type I patients [11] and from Niemann-Pick and Sandhoff mouse models [8,9] contains elevated amounts of the phospholipid phosphatidylcholine (1, PC), suggesting that high PC levels in pulmonary surfactant are the underlying cause of the pulmonary complications associated with these illnesses.…”

“…Bronchoalveolar lavage fluid collected from Sandhoff disease, and Gaucher disease type I patients [11] and from Niemann-Pick and Sandhoff mouse models [8,9] contains elevated amounts of the phospholipid phosphatidylcholine (1, PC), suggesting that high PC levels in pulmonary surfactant are the underlying cause of the pulmonary complications associated with these illnesses. Similarly, in drug-induced phospholipidosis, an acquired lysosomal storage disorder that is triggered by the administration of cationic, amphiphilic medications [13], pulmonary complications are thought to be related to increased quantities of phosphatidylcholine [14].…”

“…In Sandhoff disease, defective activity of the acid hydrolase β-hexosaminidase results in the lysosomal accumulation of the gangliosides GM 2 and GA 2 , while in Gaucher disease type I, lysosomal accumulation of glucosylceramide is due to reduced activity of the acid hydrolase glucocerebrosidase. Notwithstanding, the lung pathology associated with lysosomal build-up of PC in Niemann-Pick disease types A and B, Sandhoff disease, and Gaucher disease can result in serious clinical manifestations which include reduced pulmonary function, respiratory failure, and frequent respiratory infections that can lead to death [3,[5][6][7][8][9][10][11][12].…”