Fig. 4

The non-cell-autonomous mechanisms of UMN hyperexcitability in ALS: Oligodendrocyte dysfunction. Representation of oligodendrocyte-neuron interaction in ALS. A Defective oligodendrocytes can lead to myelin degeneration, resulting in changes in the number, distribution, length, and thickness of myelin sheaths. This directly disrupts action potential conduction along the axon and alters upper motor neuron (UMN) excitability. B Defective oligodendrocytes become less effective in regulating the composition and structure of the nodes of Ranvier. Demyelination induced paranodal junction destabilization leads to a significant disruption of Na⁺ channel clustering in the node. Oligodendrocytes also lost their ability to regulate white matter K⁺ buffering by clearing extracellular K⁺ through Kir4.1 channels. C Defective oligodendrocytes become less effective in providing metabolic support to axons through lactate transporters