51. Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease.
- Author
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Teixeira CA, Miranda CO, Sousa VF, Santos TE, Malheiro AR, Solomon M, Maegawa GH, Brites P, and Sousa MM
- Subjects
- Animals, Axons pathology, Cells, Cultured, Disease Models, Animal, Dyneins metabolism, Female, Ganglia, Spinal pathology, Ganglia, Spinal physiopathology, Leukodystrophy, Globoid Cell pathology, Male, Membrane Microdomains pathology, Membrane Microdomains physiology, Mice, Mice, Neurologic Mutants, Motor Neurons pathology, Motor Neurons physiology, Neurites pathology, Neurites physiology, Neurons pathology, Neurons physiology, Sciatic Nerve injuries, Sciatic Nerve pathology, Sciatic Nerve physiopathology, Synaptic Vesicles pathology, Synaptic Vesicles physiology, Transport Vesicles pathology, Transport Vesicles physiology, Tubulin metabolism, Axonal Transport physiology, Axons physiology, Endocytosis physiology, Leukodystrophy, Globoid Cell physiopathology, Microtubules metabolism
- Abstract
In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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