Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease

Carla Andreia Teixeira, Catarina Oliveira Miranda, Vera Filipe Sousa, Telma Emanuela Santos, Ana Rita Malheiro, Melani Solomon, Gustavo H. Maegawa, Pedro Brites, Mónica Mendes Sousa

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)92-103
Number of pages12
JournalNeurobiology of Disease
Volume66
DOIs
StatePublished - Jun 2014

Keywords

  • Axonal transport
  • Endocytosis
  • Krabbe's disease
  • Leukodystrophy
  • Myelin
  • Twitcher

ASJC Scopus subject areas

  • Neurology

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    Teixeira, C. A., Miranda, C. O., Sousa, V. F., Santos, T. E., Malheiro, A. R., Solomon, M., Maegawa, G. H., Brites, P., & Sousa, M. M. (2014). Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease. Neurobiology of Disease, 66, 92-103. https://doi.org/10.1016/j.nbd.2014.02.012