Open AccessN‐CAM Dysfunction and Unexpected Accumulation of PSA‐NCAM in Brain of Adult‐Onset Autosomal‐Dominant Leukodystrophy
Author(s) -
Piccinini Marco,
Buccinnà Barbara,
De Marco Giovanni,
Lupino Elisa,
Ramondetti Cristina,
Grifoni Silvia,
Votta Barbara,
Giordana Maria Teresa,
Rinaudo Maria Teresa
Publication year - 2010
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2009.00313.x
Subject(s) - neural cell adhesion molecule , myelin , gene isoform , biology , gene , microbiology and biotechnology , endocrinology , central nervous system , genetics , cell , cell adhesion
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.