title: Pelizaeus-Merzbacher disease-associated proteolipid protein 1 inhibits oligodendrocyte precursor cell differentiation via extracellular-signal regulated kinase signaling.
abstract: Oligodendrocytes (OLs) are myelin-forming glial cells in the central nervous system (CNS) and their dysfunction causes neuropathies such as demyelinating diseases. Proteolipid protein 1 (PLP1) is an oligodendrocyte myelin-rich tetraspan membrane protein and aberration of the plp1 gene is known to be responsible for dysmyelinating Pelizaeus-Merzbacher disease (PMD). Among previously identified gene alternations, multiplication of the plp1 gene causes increased expression of PLP1, resulting in a phenotype with severe dysmyelination in human and also rodent models. Yet little is known about the relationship between increased PLP1 expression and oligodendrocyte precursor cell (OPC) differentiation and the intracellular molecular mechanism. Here we show that expression of PLP1 in OPCs markedly inhibits their differentiation, and that this inhibitory effect is effectively improved by inhibition of extracellular signal-regulated kinase (ERK) activity. Furthermore, in cocultures with dorsal root ganglion (DRG) neurons, ERK inhibition also improves PLP1-induced dysmyelination. Thus, ERK inhibition helps to improve defective OPC differentiation induced by PLP1 expression, suggesting that molecules belonging to ERK signaling cascade may be new PMD therapeutic targets.
authors: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors: Yuki
authors: Y
authors: Miyamoto
authors: Tomohiro
authors: T
authors: Torii
authors: Akito
authors: A
authors: Tanoue
authors: Junji
authors: J
authors: Yamauchi
mesh_terms: D002454:Cell Differentiation; D018920:Coculture Techniques; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D018991:Myelin Proteolipid Protein / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D009836:Oligodendroglia / Q000166:cytology*; D020371:Pelizaeus-Merzbacher Disease / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases