The Influence of Axonal Signals and PMP2 in the Regulation of Schwann Cell Energetic Metabolism
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Issue Date
2022-05
Authors
Garfolo, Rebekah '22
Degree
MS in Pharmaceutical Sciences
Advisor
Voigt, Jeffrey
Committee Members
Poitelon, Yannick
Purrington, Lauren
Dearborn, Richard
Purrington, Lauren
Dearborn, Richard
Journal Title
Journal ISSN
Volume Title
Abstract
Schwann cells (SCs) are the myelinating cells in the peripheral nervous system. The myelination process is metabolically highly demanding and defects in SC energetic metabolism are known to contribute to the development of peripheral neuropathies. However, these exact mechanisms remain understudied. Axonal neuregulin-1 type III (NRG1tIII) is a key regulator of SC myelination and has been shown to determine sheath thickness. Overexpression of NRG1tIII results in the upregulation of peripheral myelin protein 2 (PMP2), a SC-specific fatty acid binding protein (FABP) that has been implicated in myelin formation. However, it is unclear if NRG1tIII and PMP2 modulate SC metabolism.
It was hypothesized that (i) NRG1tIII-mediated myelination and remyelination are regulated in part through Schwann cell energetic metabolism, and that (ii) PMP2 modulates Schwann cell mitochondrial ATP production. Seahorse live-cell metabolic technology was used to measure mitochondrial and glycolytic ATP production in sciatic nerve fibers isolated from WT, Pmp2-/-, NRG1tIIIOE, and NRG1tIIIOE/Pmp2-/- animal models during developmental myelination (7 days old) and remyelination (7 days after nerve crush injury).
A metabolic shift from mitochondrial to glycolytic ATP production in NRG1tIIIOE/Pmp2-/- nerves compared to NRG1tIIIOE nerves during developmental myelination suggests the absence of PMP2 promotes the use of glycolysis to maintain energetic demands. This same shift was observed in NRG1tIIIOE nerves during remyelination, likely to provide metabolic support to the regenerating axons. Interestingly, NRG1tIIIOE/Pmp2-/- nerves did not exhibit any further changes in metabolic patterns, making it unclear if this favored use of glycolysis was due to the loss of PMP2 or the enhanced metabolic demands of regenerating axons.
Additional metabolic assays were conducted on PMP2 overexpressing and control primary rat SCs to determine the SC-specific metabolic effect of PMP2. Although cells overexpressing PMP2 had elevated rates of both mitochondrial and glycolytic ATP production, they had a similar dependency (how much cells need) on and capacity (how much cells can use) to use fatty acids as substrates for mitochondrial respiration compared to the controls. These data suggest PMP2 does regulate SC-specific metabolism, but that SCs may not primarily rely on fatty acids as substrates for mitochondrial respiration.
Further studies are necessary to characterize the full effect of the protein, but PMP2 does seem to have metabolic implications in regulating SC energy production in-vitro and in-vivo. This could make PMP2 a potential therapeutic target for peripheral neuropathies.
Citation
Garfolo R. The influence of axonal signals and PMP2 in the regulation of Schwann cell energetic metabolism [thesis]. Ann Arbor (MI): Proquest LLC; 2022. 90 p.
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