title: Defective calcium homeostasis in the cerebellum in a mouse model of Niemann-Pick A disease.
abstract: We recently demonstrated that calcium homeostasis is altered in mouse models of two sphingolipid storage diseases, Gaucher and Sandhoff diseases, owing to modulation of the activities of a calcium-release channel (the ryanodine receptor) and of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) respectively, by the accumulating sphingolipids. We now demonstrate that calcium homeostasis is also altered in a mouse model of Niemann-Pick A disease, the acid sphingomyelinase (A-SMase)-deficient mouse (ASM-/-), with reduced rates of calcium uptake via SERCA in the cerebellum of 6-7-month-old mice. However, the mechanism responsible for defective calcium homeostasis is completely different from that observed in the other two disease models. Thus, levels of SERCA expression are significantly reduced in the ASM-/- cerebellum by 6-7 months of age, immediately before death of the mice, as are levels of the inositol 1,4,5-triphosphate receptor (IP3R), the major calcium-release channel in the cerebellum. Systematic analyses of the time course of loss of SERCA and IP3R expression revealed that loss of the IP3R preceeded that of SERCA, with essentially no IP3R remaining by 4 months of age, whereas SERCA was still present even after 6 months. Expression of zebrin II (aldolase C), a protein found in about half of the Purkinje cells in the adult mouse cerebellum, was essentially unchanged during development. We discuss possible pathological mechanisms related to calcium dysfunction that may cause Purkinje cell degeneration, and as a result, the onset of neuropathology in Niemann-Pick A disease.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Luba
authors.initials: L
authors.lastname: Ginzburg
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002531:Cerebellum / Q000502:physiology*; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics; D016707:Tissue Fixation
chemical_list: D009419:Nerve Tissue Proteins; C071871:zebrin II; D013108:Sphingomyelin Phosphodiesterase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium