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

by 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

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.

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