title: Peripheral neuropathy in the Twitcher mouse involves the activation of axonal caspase 3.
abstract: Infantile Krabbe disease results in the accumulation of lipid-raft-associated galactosylsphingosine (psychosine), demyelination, neurodegeneration and premature death. Recently, axonopathy has been depicted as a contributing factor in the progression of neurodegeneration in the Twitcher mouse, a bona fide mouse model of Krabbe disease. Analysis of the temporal-expression profile of MBP (myelin basic protein) isoforms showed unexpected increases of the 14, 17 and 18.5 kDa isoforms in the sciatic nerve of 1-week-old Twitcher mice, suggesting an abnormal regulation of the myelination process during early postnatal life in this mutant. Our studies showed an elevated activation of the pro-apoptotic protease caspase 3 in sciatic nerves of 15- and 30-day-old Twitcher mice, in parallel with increasing demyelination. Interestingly, while active caspase 3 was clearly contained in peripheral axons at all ages, we found no evidence of caspase accumulation in the soma of corresponding mutant spinal cord motor neurons. Furthermore, active caspase 3 was found not only in unmyelinated axons, but also in myelinated axons of the mutant sciatic nerve. These results suggest that axonal caspase activation occurs before demyelination and following a dying-back pattern. Finally, we showed that psychosine was sufficient to activate caspase 3 in motor neuronal cells in vitro in the absence of myelinating glia. Taken together, these findings indicate that degenerating mechanisms actively and specifically mediate axonal dysfunction in Krabbe disease and support the idea that psychosine is a pathogenic sphingolipid sufficient to cause axonal defects independently of demyelination.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, Chicago, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Smith
authors.forename: Francesca
authors.initials: F
authors.lastname: Galbiati
authors.forename: Ludovico Cantuti
authors.initials: LC
authors.lastname: Castelvetri
authors.forename: Maria I
authors.initials: MI
authors.lastname: Givogri
authors.forename: Aurora
authors.initials: A
authors.lastname: Lopez-Rosas
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Bongarzone
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D002461:Cell Line, Transformed; D002518:Ceramides / Q000494:pharmacology; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007965:Leukodystrophy, Globoid Cell / Q000150:complications* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D009431:Neural Conduction / Q000502:physiology; D016900:Neurofilament Proteins / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000209:etiology* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011609:Psychosine / Q000494:pharmacology; D012584:Sciatic Nerve / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D002518:Ceramides; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D020033:Protein Isoforms; C044882:neurofilament protein L; C101954:N-caproylsphingosine; D011609:Psychosine; D053148:Caspase 3