title: N-CAM dysfunction and unexpected accumulation of PSA-NCAM in brain of adult-onset autosomal-dominant leukodystrophy.
abstract: Previously, myelin from cerebral white matter (CWM) of two subjects of a family with orthochromatic adult-onset autosomal-dominant leukodystrophy (ADLD) was disclosed to exhibit defective large isoform of myelin-associated glycoprotein (L-MAG) and patchy distribution only in the elder subject. L-MAG and neural cell adhesion molecule (N-CAM) (N-CAM 180, 140, and 120) are structurally related and concur to myelin/axon interaction. In early developmental stages, in neurons and glia N-CAM is converted into polysialylated (PSA)-NCAM by two sialyltransferases sialyltransferase-X (STX) and polysialyltransferase-1 (PST). Notably, PSA-NCAM disrupts N-CAM adhesive properties and is nearly absent in the adult brain. Here, CWM extracts and myelin of the two subjects were searched for the expression pattern of the N-CAM isoforms and PSA-NCAM, and their CWM was evaluated for N-CAM, STX and PST gene copy number and gene expression as mRNA. Biochemically, we disclosed that in CWM extracts and myelin from both subjects, PSA-NCAM accumulates, N-CAM 180 considerably increases, N-CAM 140 is modestly modified and N-CAM 120 remarkably decreases; duplication of genes encoding N-CAM, STX and PST was not revealed, whereas PST mRNA was clearly increased. Immunohistochemically, in CWM of both subjects, we found an unusually diffuse accumulation of PSA-NCAM without inflammation markers. PSA-NCAM persistence, up-regulated PST mRNA and previously uncovered defective L-MAG may be early pathogenetic events in this ADLD form.
authors.affiliation: Department of Medicine and Experimental Oncology, Section of Biochemistry, University of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Piccinini
authors.forename: Barbara
authors.initials: B
authors.lastname: Buccinnà
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Marco
authors.forename: Elisa
authors.initials: E
authors.lastname: Lupino
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramondetti
authors.forename: Silvia
authors.initials: S
authors.lastname: Grifoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Votta
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Giordana
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Rinaudo
mesh_terms: D000328:Adult; D017668:Age of Onset; D015153:Blotting, Western; D054022:Cerebrum / Q000378:metabolism*; D005190:Family; D018628:Gene Dosage; D005786:Gene Expression Regulation; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D056784:Leukoencephalopathies / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012794:Sialic Acids / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018992:Myelin-Associated Glycoprotein; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D020033:Protein Isoforms; D012333:RNA, Messenger; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases; C551345:polysialyltransferase-1, human