RRC ID 82620
Author Miyamoto Y, Tanaka M, Ito H, Ooizumi H, Ohbuchi K, Mizoguchi K, Torii T, Yamauchi J.
Title Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice.
Journal Biochem Biophys Res Commun
Abstract Pelizaeus-Merzbacher disease (PMD) is characterized as a congenital hypomyelinating disorder in oligodendrocytes, myelin-forming glial cells in the central nervous system (CNS). The responsible gene of PMD is plp1, whose multiplication, deletion, or mutation is associated with PMD. We previously reported that primary oligodendrocytes overexpressing proteolipid protein 1 (PLP1) do not have the ability to differentiate morphologically, whereas inhibition of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) by its cognate siRNA or chemical inhibitor reverses their undifferentiated phenotypes. Here, we show that oligodendrocyte-specific expression of kinase-deficient dominant-inhibitory mutant (MEK2K101A) of MAPK/ERK kinase 2 (MEK2), as the direct upstream molecule of MAPK/ERK in PMD model mice, promotes myelination in CNS tissues. Expression of MEK2K101A in PMD model mice also improves Rotor-rod test performance, which is often used to assess motor coordination in a rodent model with neuropathy. These results suggest that in PMD model mice, MEK2K101A can ameliorate impairments of myelination and motor function and that the signaling through MAPK/ERK may involve potential therapeutic target molecules of PMD in vivo.
Volume 531(4)
Pages 445-451
Published 2020-10-22
DOI 10.1016/j.bbrc.2020.07.131
PII S0006-291X(20)31532-1
PMID 32800341
MeSH Animals Brain / pathology Disease Models, Animal Female Gene Expression Regulation, Enzymologic Genes, Dominant MAP Kinase Kinase 2 / genetics* MAP Kinase Kinase 2 / metabolism MAP Kinase Signaling System / genetics Male Mice, Transgenic Mutation Myelin Proteolipid Protein / genetics Myelin Sheath / metabolism Myelin Sheath / pathology Pelizaeus-Merzbacher Disease / etiology* Phenotype Rotarod Performance Test
Resource
Mice RBRC00999