Introduction/Aim: Mucopolysaccharidosis type IIIA (MPS IIIA), is a lysosomal storage disorder caused by a deficiency in the activity of sulphamidase. This results in primary storage of heparan sulphate and secondary storage of gangliosides GM2 & GM3 and cholesterol in brain and liver. MPS IIIA patients also exhibit airway obstruction, restrictive lung disease, and in severe cases respiratory infections may lead to death in children. However, pulmonary storage has not been demonstrated and the underlying cellular mechanisms of respiratory pathology have not been investigated. This study aimed to characterise storage material and ultrastructure of MPS IIIA lung tissue in a mouse model.
Methods: Lung tissue was from 15 week old controls and congenic C57BL/6J MPS IIIA mice. Storage of heparan sulphate, cholesterol and gangliosides was characterised by ESI-MS/MS. Histological and ultrastructural analyses were performed using light and electron microscopy, respectively.
Results: Lung tissue heparan sulphate was significantly greater in MPS IIIA than in control mice (69.14 ± 7.88 vs 0.38±0.03; n=10, p<0.05). Free cholesterol was elevated in lung tissue of MPSIIIA relative to control mice (120.67±12.33 vs 84.73±4.49 nmol/mg protein, n=3, p=0.05). The C18:0/18:1 moieties of GM1, 2 & 3 were elevated in MPS IIIA compared with control lung tissue (n=3, p<0.05). Ultrastructurally, we observed electron lucent vesicles consistent with heparan sulphate storage, increased collagen deposition and abnormal lamellar bodies in alveolar type II cells in MPS IIIA tissue compared with control tissue.
Conclusion: We have, for the first time, demonstrated storage of heparan sulphate, gangliosides and cholesterol in MPS IIIA mouse lung; observed abnormal lamellar bodies and increased collagen deposition in lung parenchyma. Disorganised lamellar bodies are a likely consequence of altered surfactant lipid and protein metabolism. This may have implications for surfactant and lung function, which may be an underlying reason for the observed respiratory pathology in MPS IIIA.