Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice

• Published in: Biochemical and biophysical research communications 2020-10, Vol.531 (4), p.445-451
• Main Authors: Miyamoto, Yuki, Tanaka, Marina, Ito, Hisanaka, Ooizumi, Hiroaki, Ohbuchi, Katsuya, Mizoguchi, Kazushige, Torii, Tomohiro, Yamauchi, Junji
• Format: Article
• Language: English
• Subjects: Animals; Brain - pathology; Disease Models, Animal; Female; Gene Expression Regulation, Enzymologic; Genes, Dominant; Male; MAP Kinase Kinase 2 - genetics; MAP Kinase Kinase 2 - metabolism; MAP Kinase Signaling System - genetics; Mice, Transgenic; Mitogen-activated protein kinase; Mutation; Myelin Proteolipid Protein - genetics; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelination; Oligodendrocyte; Pelizaeus-Merzbacher disease; Pelizaeus-Merzbacher Disease - etiology; Phenotype; Rotarod Performance Test; Transgenic mouse
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.07.131

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. •Dominant-inhibitory mutant of MEK2 (MEK2K101A)-transgenic mice have been generated.•MEK2K101A inhibits MAPK hyperphosphorylation in PMD model mice.•MEK2K101A ameliorates myelinating states in PMD model mouse tissues.•MEK2K101A ameliorates Rotor-rod performance in PMD model mice.