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The Sphingolipid Psychosine Inhibits Fast Axonal Transport in Krabbe Disease by Activation of GSK3 and Deregulation of Molecular Motors

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posted on 20.11.2013 by Ludovico Cantuti Castelvetri, Maria I. Givogri, Amy Hebert, Benjamin Smith, Yuyu Song, Agnieszka Kaminska, Aurora Lopez-Rosas, Gerardo Morfini, Gustavo Pigino, Mark Sands, Scott T. Brady, Ernesto R. Bongarzone
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 GSK3 beta in the axon. Abnormal levels of activated GSK3 beta and abnormally phosphorylated kinesin light chains were found in nerve samples from a mouse model of Krabbe disease. Administration of GSK3 beta 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.

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Funding

This work was supported by a Chancellor Award (to L.C.C.), the National Institutes of Health (Grant #RNS065808A), the Morton Cure Paralysis Foundation, the Legacy of Angels Foundation, and the Board of Trustees at the University of Illinois (to E.R.B.).

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Publisher Statement

This is a copy of an article published in the Journal of Neuroscience © 2013 Society for Neuroscience. The original version is available at http://www.jneurosci.org/ doi: 10.1523/JNEUROSCI.0217-13.2013

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Society for Neuroscience

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en_US

issn

0270-6474

Issue date

01/06/2013

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