ArticleNeurobiology of disease2014
Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease.
Article in Neurobiology of disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 63 citations in OpenAlex.
- Sphingolipid-neutralizing molecular therapy reduces psychosine cytotoxicity in Krabbe disease.iScience · 2026Article
- Review
- Ablation of lipocalin-2 reduces neuroinflammation in a mouse model of Krabbe disease.Scientific reports · 2024Article
- Linking glycosphingolipid metabolism to disease-related changes in the plasma membrane proteome.Biochemical Society transactions · 2024Review
- Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2023Review
- Article
- HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease.Frontiers in molecular neuroscience · 2023Article
- Secondary Mitochondrial Dysfunction as a Cause of Neurodegenerative Dysfunction in Lysosomal Storage Diseases and an Overview of Potential Therapies.International journal of molecular sciences · 2022Review
- Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases.Journal of controlled release : official journal of the Controlled Release Society · 2022Article
- Neurons contribute to pathology in a mouse model of Krabbe disease in a cell-autonomous manner.PLoS biology · 2022Article
- Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration.PLoS biology · 2022Article
- Synaptic Vesicle Recycling and the Endolysosomal System: A Reappraisal of Form and Function.Frontiers in synaptic neuroscience · 2022Review
- Review
- Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission.JCI insight · 2021Article
- Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.Stem cell reports · 2021Article
- Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.Frontiers in medicine · 2021Review
- Synaptic Function and Dysfunction in Lysosomal Storage Diseases.Frontiers in cellular neuroscience · 2021Article
- Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease.Nature communications · 2020Article
- Article
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.