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Published on: November 9, 2020
Pharmacological Targeting of PI3K/Akt/mTOR and Wnt/GSK-3β Signaling in Oligodendrocyte Differentiation and
1Immunology Research Lab & BK21-Four Educational Research Group for Age-Associated Disorder Control Technology, Department of Biological Science, Chosun University, Gwangju 61452, Republic of Korea.
Abstract:
Demyelinating diseases are characterized by loss of myelin and impaired neuronal function. Differentiation of oligodendrocyte progenitor cells (OPCs) and neural stem and progenitor cells is regulated by intracellular kinase signaling pathways. PI3K/Akt/mTOR and Wnt/GSK-3β signaling are involved in oligodendrocyte maturation and neurogenesis, and pharmacological modulation of these pathways affects myelin formation and neuronal differentiation. Small-molecule compounds targeting these pathways influence protein synthesis, lipid production, and β-catenin-dependent transcription. Activation of Akt and mTOR is associated with increased myelin-related protein expression, whereas inhibition of mTOR reduces oligodendrocyte differentiation. In contrast, inhibition of GSK-3β affects β-catenin stability and is associated with oligodendrocyte differentiation. These pathways also affect proliferation and differentiation of neural stem and progenitor cells. However, effects observed in experimental demyelination models have not been established as direct evidence of remyelination in patients. In addition, pharmacological agents act on multiple cell populations in the central nervous system (CNS), which complicates interpretation of their effects on specific cell types. This review examines pharmacological targeting of PI3K/Akt/mTOR and Wnt/GSK-3β signaling and describes intracellular mechanisms involved in oligodendrocyte and neuronal differentiation, with consideration of therapeutic application in demyelinating diseases.
Insights
Targeting PI3K/Akt/mTOR and Wnt/GSK-3β pathways shows potential for treating demyelinating diseases by influencing oligodendrocyte and neural stem cell differentiation. Further research is needed to confirm remyelination in patients.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Demyelinating diseases cause myelin loss and impair neuronal function.
- Oligodendrocyte progenitor cells (OPCs) and neural stem cells differentiate via kinase signaling pathways.
- PI3K/Akt/mTOR and Wnt/GSK-3β pathways are crucial for myelin formation and neurogenesis.
Purpose of the Study:
- To review the pharmacological targeting of PI3K/Akt/mTOR and Wnt/GSK-3β signaling pathways.
- To describe intracellular mechanisms in oligodendrocyte and neuronal differentiation.
- To consider therapeutic applications for demyelinating diseases.
Main Methods:
- Literature review of studies on PI3K/Akt/mTOR and Wnt/GSK-3β signaling.
- Analysis of intracellular mechanisms regulating cell differentiation.
- Examination of pharmacological modulation effects.
Main Results:
- Activation of Akt/mTOR increases myelin protein expression; mTOR inhibition reduces oligodendrocyte differentiation.
- GSK-3β inhibition impacts β-catenin stability, promoting oligodendrocyte differentiation.
- These pathways influence neural stem and progenitor cell proliferation and differentiation.
Conclusions:
- Pharmacological targeting of these pathways offers therapeutic potential for demyelinating diseases.
- Understanding intracellular mechanisms is key to developing effective treatments.
- Translating experimental findings to patient remyelination requires further investigation.
