Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice
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Published on: July 17, 2019
Yuki Miyamoto1, Marina Tanaka2, Hisanaka Ito3
1Laboratory of Molecular Neuroscience and Neurology, Hachioji, Tokyo, 192-0392, Japan; Laboratory of Molecular Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, 157-8535, Japan.
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.
Insights
Inhibition of MAPK/ERK signaling via MEK2K101A expression promotes myelination and improves motor function in Pelizaeus-Merzbacher disease (PMD) mouse models, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Pelizaeus-Merzbacher disease (PMD) is a congenital hypomyelinating disorder caused by mutations in the PLP1 gene, affecting oligodendrocytes and central nervous system (CNS) myelination.
- Overexpression of proteolipid protein 1 (PLP1) in oligodendrocytes impairs their differentiation, and inhibition of the MAPK/ERK pathway can reverse this phenotype.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting the MAPK/ERK pathway in PMD.
- To evaluate the effect of oligodendrocyte-specific expression of a dominant-inhibitory MEK2 mutant (MEK2K101A) on myelination and motor function in PMD model mice.
Main Methods:
- Utilized PMD model mice with oligodendrocyte-specific expression of kinase-deficient MEK2 (MEK2K101A).
- Assessed central nervous system (CNS) myelination.
- Evaluated motor coordination using the Rotor-rod test.
Main Results:
- Oligodendrocyte-specific expression of MEK2K101A promoted myelination in the CNS of PMD model mice.
- MEK2K101A expression improved motor coordination performance in PMD model mice.
- These findings indicate that MEK2K101A ameliorates myelination and motor function impairments in vivo.
Conclusions:
- Inhibition of the MAPK/ERK signaling pathway through MEK2K101A expression is a promising therapeutic strategy for Pelizaeus-Merzbacher disease.
- The MAPK/ERK pathway represents a potential therapeutic target for improving myelination and motor function in PMD.
