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

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...

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Bibliographic Details
Published in:PLoS biology 2020-11, Vol.18 (11), p.e3000943-e3000943
Main Authors: Trevisiol, Andrea, Kusch, Kathrin, Steyer, Anna M, Gregor, Ingo, Nardis, Christos, Winkler, Ulrike, Köhler, Susanne, Restrepo, Alejandro, Möbius, Wiebke, Werner, Hauke B, Nave, Klaus-Armin, Hirrlinger, Johannes
Format: Article
Language:English
Subjects:
Action Potentials
Adenosine Triphosphate - metabolism
Animals
ATP
Axons
Axons - metabolism
Biology and Life Sciences
Deprivation
Disease Models, Animal
Energy
Energy Metabolism
Energy recovery
Energy requirements
Engineering and Technology
Female
Fluorescence
Fluorescence lifetime sensing devices
Glucose
Homeostasis
Male
Medicine and Health Sciences
Metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Electron, Transmission
Microscopy, Immunoelectron
Myelin
Myelin proteolipid protein
Myelin Proteolipid Protein - deficiency
Myelin Proteolipid Protein - genetics
Myelin Sheath - metabolism
Myelin Sheath - pathology
Nerves
Nervous system
Neurological diseases
Neurological disorders
Optic nerve
Optic Nerve - metabolism
Optic Nerve - pathology
Paralysis
Paraplegia - genetics
Paraplegia - metabolism
Paraplegia - pathology
Paraplegics
pH effects
Phenotype
Proteins
Research and Analysis Methods
Sensors
Social Sciences
Spastic paraplegia
Spasticity
Transgenic mice
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Summary: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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3000943