Increased lung surfactant phosphatidylcholine in patients affected by lysosomal storage diseases

Abstract

Sandhoff disease, Gaucher disease type I and sialidosis type I are lysosomal storage disorders caused, respectively, by deficiency of activity of beta-hexosaminidase (storage of GM(2) and GA(2) ganglioside), glucosylceramidase (storage of glucosylceramide) and alpha-neuraminidase (storage of glucopeptides and/or oligosaccharides). Progressive clinical systemic and neurological dysfunctions are observed. In these pathologies, respiratory infections often lead to death. Elevation of the lung surfactant phosphatidylcholine (PC) has previously been reported in the Hexb mouse, a model of Sandhoff disease. We evaluated phospholipids in the lung surfactant of patients affected by the described lysosomal diseases, observing a statistically significant increase of total lipid phosphate in the patients as compared with controls. Moreover, higher levels of PC in patients affected by sialidosis (3.6-fold) and Gaucher (4-fold) disease, and of PC (4.15-fold) and phosphatidylethanolamine (2.3-fold) in a patient affected by Sandhoff disease were noted. The latter confirms the previous results in the Hexb mouse. We suggest that changes in phospholipid metabolism can be common in different lysosomal storage disorders and can increase the susceptibility to respiratory infections, usually present in these disorders.

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

“…A similar increase in lung phospholipids has been found in mouse models of these diseases as, for example, the ␤-hexosaminidase-deficient mouse (50). We have recently evaluated pearl mice that are a model of the Hermansky-Pudlak syndrome, a disease of protein trafficking and organellar dysfunction (52).…”

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

“…Genetic mutations in the human NEU1 locus lead to the lysosomal storage disease sialidosis (70). Sialidosis patients with the early onset form of the disease have a mucopolysaccharidosis-like phenotype with a subset of cases presenting with respiratory complications (71). In Neu1 Ϫ/Ϫ mice, normal alveolar wall septation does not occur, resulting in enlarged alveoli that are maintained in adults due to the requirement of Neu1 for normal assembly of elastic fibers (72).…”

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].…”