The Sphingolipid Psychosine Inhibits Fast Axonal Transport in Krabbe Disease by Activation of GSK3β and Deregulation of Molecular Motors

Overview

Journal J Neurosci

Specialty Neurology

Date 2013 Jun 14

PMID 23761900

Citations 56

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

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