title: Exocytosis is impaired in mucopolysaccharidosis IIIA mouse chromaffin cells.
abstract: Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder caused by a deficiency in the activity of the lysosomal hydrolase, sulphamidase, an enzyme involved in the degradation of heparan sulphate. MPS IIIA patients exhibit progressive mental retardation and behavioural disturbance. While neuropathology is the major clinical problem in MPS IIIA patients, there is little understanding of how lysosomal storage generates this phenotype. As reduced neuronal communication can underlie cognitive deficiencies, we investigated whether the secretion of neurotransmitters is altered in MPS IIIA mice; utilising adrenal chromaffin cells, a classical model for studying secretion via exocytosis. MPS IIIA chromaffin cells displayed heparan sulphate storage and electron microscopy revealed large electron-lucent storage compartments. There were also increased numbers of large/elongated chromaffin granules, with a morphology that was similar to immature secretory granules. Carbon fibre amperometry illustrated a significant decrease in the number of exocytotic events for MPS IIIA, when compared to control chromaffin cells. However, there were no changes in the kinetics of release, the amount of catecholamine released per exocytotic event, or the amount of Ca(2+) entry upon stimulation. The increased number of large/elongated granules and reduced number of exocytotic events suggests that either the biogenesis and/or the cell surface docking and fusion potential of these vesicles is impaired in MPS IIIA. If this also occurs in central nervous system neurons, the reduction in neurotransmitter release could help to explain the development of neuropathology in MPS IIIA.
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Keating
authors.forename: M A
authors.initials: MA
authors.lastname: Winter
authors.forename: K M
authors.initials: KM
authors.lastname: Hemsley
authors.forename: K D
authors.initials: KD
authors.lastname: Mackenzie
authors.forename: E H
authors.initials: EH
authors.lastname: Teo
authors.forename: J J
authors.initials: JJ
authors.lastname: Hopwood
authors.forename: D A
authors.initials: DA
authors.lastname: Brooks
authors.forename: E J
authors.initials: EJ
authors.lastname: Parkinson-Lawrence
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002244:Carbon; D000077482:Carbon Fiber; D002395:Catecholamines / Q000378:metabolism; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000502:physiology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005089:Exocytosis / Q000235:genetics*; D006497:Heparan Sulfate / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009084:Mucopolysaccharidosis III / Q000235:genetics* / Q000473:pathology*; D018709:Statistics, Nonparametric
chemical_list: D002118:Calcium; D002244:Carbon; D000077482:Carbon Fiber; D002395:Catecholamines; D006497:Heparan Sulfate