title: Neuroaxonal dystrophy in calcium-independent phospholipase A2β deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes.
abstract: Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6 [calcium-independent phospholipase A(2)β (iPLA(2)β)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA(2)β knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS)-positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acid-containing phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA(2)β deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA(2)β-KO mice.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Beck
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Koei
authors.initials: K
authors.lastname: Shinzawa
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Setou
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.forename: Hisae
authors.initials: H
authors.lastname: Sumi-Akamaru
mesh_terms: D000367:Age Factors; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D054522:Group VI Phospholipases A2 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D008954:Models, Biological; D019150:Neuroaxonal Dystrophies / Q000150:complications / Q000235:genetics / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000209:etiology*; D017729:Presynaptic Terminals / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000447:Aldehydes; D018160:Receptors, Cytoplasmic and Nuclear; D004281:Docosahexaenoic Acids; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; C027576:4-hydroxy-2-nonenal; D002118:Calcium