Myelination and mTOR

Abstract

Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

“…While hyperactivation of mTOR by deleting TSC2 leads to increased p‐S6 kinase but decreased p‐AKT, leading to hypomyelination (Beirowski et al, ). One mechanism that has been suggested that is that p‐S6 kinase (p‐S6K) can inhibit p‐AKT signaling via a negative feedback loop (Figlia et al, ). Phospho‐S6K can phosphorylate and degrade IRS1 (Copps & White, ), which is downstream of INSR/IGF1R but upstream of p‐AKT.…”

“…We observed that INSR/IGF1R SCKO mice have reduced p-AKT, p-mTOR, SREBP1, and lower expression of genes that regulate fatty acid and cholesterol synthesis. mTOR signaling must be carefully regulated in a stage-specific manner to ensure proper initiation and maintenance of myelin (Beirowski et al, 2017;Figlia et al, 2017;Figlia, Gerber, & Suter, 2018). Hyperactivation of mTOR by deleting PTEN leads to increased p-AKT and p-S6 kinase and subsequently hypermyelination (Goebbels et al, 2012).…”

The mechanistic target of rapamycin pathway downregulates bone morphogenetic protein signaling to promote oligodendrocyte differentiation

“…mTOR, as a component of the protein complexes mTORC1 and mTORC2, is a central regulator of cellular response to upstream pathways including growth factor receptor signaling and nutrient sensing. It is an ubiquitously expressed serine/threonine protein kinase and promotes myelination in the central and peripheral nervous systems (Figlia et al, ; Guardiola‐Diaz, Ishii, & Bansal, ; Narayanan, Flores, Wang, & Macklin, ; Sherman et al, ; Tyler et al, ; Tyler et al, ; Wahl et al, ). mTOR hyperactivation in oligodendroglia, through either constitutive activation of Akt or deletion of PTEN, results in increased myelination (Flores et al, ; Goebbels et al, ; Harrington et al, ).…”

“…Conversely, a major pathway that promotes oligodendrocyte differentiation and central nervous system (CNS) myelination is the PI3 kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway (recently reviewed: Figlia, Gerber, & Suter, ). Disruption of this pathway in mice compromises developmental myelination (Bercury et al, ; Lebrun‐Julien et al, ; Wahl, McLane, Bercury, Macklin, & Wood, ).…”

The TSC1‐mTOR‐PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage‐specific manner

“…mTORC1 is crucial for myelination in both central and peripheral nervous systems (Beirowski et al 2017; Bercury et al 2014; Figlia et al 2018; Lebrun-Julien et al 2014; Norrmén et al 2014; Sherman et al 2012; Wahl et al 2014). Loss of mTOR leads to profound hypomyelination in the PNS (Sherman et al 2012), and, conversely, activation of mTOR through the loss of PTEN or activation of AKT promotes hypermyelination in the PNS (Domenech-Estevez et al 2016; Goebbels et al 2010; Maurel and Salzer 2000).…”