The sphingolipid psychosine inhibits fast axonal transport in Krabbe disease by activation of GSK3β and deregulation of molecular motors

• Published in: The Journal of neuroscience 2013-06, Vol.33 (24), p.10048-10056
• Main Authors: Cantuti Castelvetri, Ludovico, Givogri, Maria I, Hebert, Amy, Smith, Benjamin, Song, Yuyu, Kaminska, Agnieszka, Lopez-Rosas, Aurora, Morfini, Gerardo, Pigino, Gustavo, Sands, Mark, Brady, Scott T, Bongarzone, Ernesto R
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Axonal Transport - drug effects; Cells, Cultured; Cerebral Cortex - pathology; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Leukodystrophy, Globoid Cell - drug therapy; Leukodystrophy, Globoid Cell - genetics; Leukodystrophy, Globoid Cell - pathology; Membrane Microdomains - drug effects; Membrane Microdomains - enzymology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron, Transmission; Mitochondria - drug effects; Mitochondria - physiology; Molecular Motor Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - pathology; Neurons - ultrastructure; Psychosine - pharmacology; Sciatic Nerve - pathology; Time Factors
• ISSN: 1529-2401; 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0217-13.2013

Loss of function of galactosylceramidase lysosomal activity causes demyelination and vulnerability of various neuronal populations in Krabbe disease. Psychosine, a lipid-raft-associated sphingolipid that accumulates in this disease, is thought to trigger these abnormalities. Myelin-free in vitro analyses showed that psychosine inhibited fast axonal transport through the activation of axonal PP1 and GSK3β in the axon. Abnormal levels of activated GSK3β and abnormally phosphorylated kinesin light chains were found in nerve samples from a mouse model of Krabbe disease. Administration of GSK3β inhibitors significantly ameliorated transport defects in vitro and in vivo in peripheral axons of the mutant mouse. This study identifies psychosine as a pathogenic sphingolipid able to block fast axonal transport and is the first to provide a molecular mechanism underlying dying-back degeneration in this genetic leukodystrophy.