Modelling saposin deficiency in Drosophila: progressive neurodegeneration, storage and physiological decline

Abstract

Saposin deficiency is a lysosomal storage disorder (LSD) characterised by the lysosomal accumulation of sphingolipids. The disorder is caused by mutations in the prosaposin gene, which encodes 4 activator proteins: saposins A - D. Mutations affecting individual saposins lead to different LSDs. Therefore, modelling saposin deficiency in Drosophila provides great scope for understanding childhood neurodegeneration. The Drosophila prosaposin homologue is the Saposin-related (dSap-r) locus, which encodes 8 putative saposins. During this investigation, dSap-r mutants were generated and characterised for classic hallmarks of LSDs. Reduced longevity and progressive neurodegeneration were identified in all dSap-r mutants. Neurodegeneration was mainly localised to sensory regions of the brain involved in olfaction and vision. Ultrastructural analysis revealed neuronal storage of electron-dense material containing numerous multivesicular and multilamellar bodies, and a gross enlargement in neuronal cell body size. The physiological implication of this progressive degeneration was a decline in sensorimotor output, measured as a reduction in climbing and jumping ability, and a deterioration in phototransduction, measured by electroretinograms. In addition to nervous system pathology, dSap-r mutants also exhibited an abdominal swelling phenotype that may be related to their abnormal Malpighian (renal) tubules and may, therefore, represent an osmoregulatory defect. Both the neurodegenerative and visceral organ pathology observed in the dSap-r mutants suggest these mutants are a valid model for the study of the saposin deficiencies and related disorders.