Intracellular distribution of myelin protein gene products is altered in oligodendrocytes of the taiep rat

Abstract

Hypomyelination and subsequent demyelination of the taiep rat CNS are thought to result from the abnormal accumulation of microtubules (MTs) in oligodendrocytes that disrupts intracellular transport of components needed to form and maintain the myelin sheath. In this study, myelin gene expression was evaluated in mutant and age-matched controls to determine if MT abnormalities affect the distribution of myelin proteins and their mRNAs. Immunohistochemical analysis of taiep brains and spinal cords revealed a gradual decrease in levels of several myelin proteins including myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and 2',3'-cyclic nucleotide 3'-phosphodiesterase. Accompanying early declines in MAG and PLP, accumulations of immunoreactive products were detected within oligodendrocytes, consistent with a defect in protein trafficking. Northern blot analysis indicated that diminishing protein levels could not be attributed to changes in transcriptional activity, except for MBP of which mRNA levels decreased with age. Cellular localization of MBP mRNA by in situ hybridization further revealed that transcripts were concentrated within oligodendrocyte cell bodies instead of uniformly distributed throughout processes. These results demonstrate that changes in expression and intracellular localization of myelin gene products are concurrent with increases in MT mass in taiep oligodendrocytes and support our hypothesis that cytoskeletal defects prevent the normal transport of elements required for the formation and maintenance of the myelin sheath.