Structural myelin defects are associated with low axonal ATP levels but rapid recovery from energy deprivation in a mouse model of spastic paraplegia

Andrea Trevisiol; Kathrin Kusch; Anna M Steyer; Ingo Gregor; Christos Nardis; Ulrike Winkler; Susanne Köhler; Alejandro Restrepo; Wiebke Möbius; Hauke B Werner; Klaus-Armin Nave; Johannes Hirrlinger

doi:10.1371/journal.pbio.3000943

Structural myelin defects are associated with low axonal ATP levels but rapid recovery from energy deprivation in a mouse model of spastic paraplegia

PLoS Biol. 2020 Nov 16;18(11):e3000943. doi: 10.1371/journal.pbio.3000943. eCollection 2020 Nov.

Authors

Andrea Trevisiol¹, Kathrin Kusch¹, Anna M Steyer^{1

2}, Ingo Gregor³, Christos Nardis^{1

2}, Ulrike Winkler⁴, Susanne Köhler⁴, Alejandro Restrepo¹, Wiebke Möbius^{1

2}, Hauke B Werner¹, Klaus-Armin Nave¹, Johannes Hirrlinger^{1

4}

Affiliations

¹ Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
² Electron Microscopy Core Facility, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
³ Third Institute of Physics, Georg August University, Göttingen, Germany.
⁴ Carl Ludwig Institute for Physiology, Faculty of Medicine, University of Leipzig, Leipzig, Germany.

Abstract

In several neurodegenerative disorders, axonal pathology may originate from impaired oligodendrocyte-to-axon support of energy substrates. We previously established transgenic mice that allow measuring axonal ATP levels in electrically active optic nerves. Here, we utilize this technique to explore axonal ATP dynamics in the Plpnull/y mouse model of spastic paraplegia. Optic nerves from Plpnull/y mice exhibited lower and more variable basal axonal ATP levels and reduced compound action potential (CAP) amplitudes, providing a missing link between axonal pathology and a role of oligodendrocytes in brain energy metabolism. Surprisingly, when Plpnull/y optic nerves are challenged with transient glucose deprivation, both ATP levels and CAP decline slower, but recover faster upon reperfusion of glucose. Structurally, myelin sheaths display an increased frequency of cytosolic channels comprising glucose and monocarboxylate transporters, possibly facilitating accessibility of energy substrates to the axon. These data imply that complex metabolic alterations of the axon-myelin unit contribute to the phenotype of Plpnull/y mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials
Adenosine Triphosphate / metabolism*
Animals
Axons / metabolism
Disease Models, Animal
Energy Metabolism
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Electron, Transmission
Microscopy, Immunoelectron
Myelin Proteolipid Protein / deficiency
Myelin Proteolipid Protein / genetics
Myelin Sheath / metabolism*
Myelin Sheath / pathology
Optic Nerve / metabolism
Optic Nerve / pathology
Paraplegia / genetics
Paraplegia / metabolism*
Paraplegia / pathology
Phenotype

Substances

Myelin Proteolipid Protein
Plp1 protein, mouse
Adenosine Triphosphate

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG, www.dfg.de: grant number Hi1414/6-1 (SPP1757) to JH; WE2720/4-1 to HBW; MO 1084/2-1 (FOR2848, P8) to WM; SFB-TR43 to KAN; Na262/1-2 (SPP1757) to KAN; Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, CNMPB, to KAN and WM) as well as the European Research Council (ERC, erc.europa.eu: ERC Advanced Grants AxoGlia and MyeliNANO to KAN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.