Peripheral neuropathy in the Twitcher mouse involves the activation of axonal caspase 3.

[krabbe disease]

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 .

Diseases
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Diseases presenting "bona fide mouse model" symptom

krabbe disease

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