Axonopathy is a compounding factor in the pathogenesis of Krabbe disease

Abstract

Loss-of-function of the lysosomal enzyme galactosyl-ceramidase (GALC) causes the accumulation of the lipid raft-associated sphingolipid psychosine, the disruption of postnatal myelination, neurodegeneration and early death in most cases of infantile Krabbe disease. This work presents a first study towards understanding the progression of axonal defects in this disease using the Twitcher mutant mouse. Axonal swellings were detected in axons within the mutant spinal cord as early as one week after birth. As the disease progressed, more axonopathic profiles were found in other regions of the nervous system, including peripheral nerves and various brain areas. Isolated mutant neurons recapitulated axonal and neuronal defects in the absence of mutant myelinating glia, suggesting an autonomous neuronal defect. Psychosine was sufficient to induce axonal defects and cell death in cultures of acutely isolated neurons. Interestigly, axonopathy in young Twitcher mice occured in the absence of demyelination and of neuronal apoptosis. Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants.

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…Psychosine treatment of oligodendrocytes has also been shown to induce the generation of LPC and arachidonic acid, and inhibition of secreted phospholipase A2 (sPLA2) attenuates psychosine-induced increases in both LPC and arachidonic acid as well as attenuating psychosine-induced cell death (Giri et al, 2006). Furthermore, psychosine accumulation has been reported to induce phosphorylation of neurofilament proteins, resulting in reduced radial growth of axons in the twi/twi mouse model and to induce axonal defects and cell death in isolated neuronal cultures (CantutiCastelvetri et al, 2012;Castelvetri et al, 2011). S1PRs are known to play many roles in the regulation of differentiation, cell survival and apoptosis of oligodendrocytes, astrocytes and microglia (Dev et al, 2008;Miron et al, 2008b).…”

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…This results in demyelination affecting both the central and peripheral nervous systems [49,50]. However, there is still discussion whether axonopathy is secondary to demyelination or if is directly caused by the GalSph accumulation in Krabbe neurons [51].…”

Original article Diagnostic difficulties in Krabbe disease: a report of two cases and review of literature

“…Castelvetri suggested that before the onset of the disease, accumulation of psychosine was below the concentration lethal for oligodendrocytes, but still sufficient to affect the structure of axons [2]. Various stages of axonal damage were described, which initiated axonal varicosities and swellings, and eventually axonal transections.…”