Abstract
Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse. We find mild effects on motorneuron soma, severe ones on sciatic nerves and very severe effects on nerve terminals and neuromuscular junctions at P30, with peripheral damage being already detectable at P15. Finally, we find that the gastrocnemius muscle undergoes atrophy and structural changes that are independent of denervation at P15. Our data further characterize the ultrastructural analysis of the KD mouse model, and support recent theories of a dying-back mechanism for neuronal degeneration, which is independent of demyelination.
Highlights
Krabbe disease (KD)[1], known as globoid cell leukodistrophy, is a neurodegenerative disorder of the leukodistrophies family mainly affecting infancy-childhood and more rarely adulthood[2,3,4]
We observed that this effect depends on four main factors: (1) the presence of cells from immune system, especially globoid cells, an established hallmark of KD; (2) higher level of collagen fibrils; (3) enlarged cytosolic portion of Schwann cells (SCs); (4) increased empty space between axons
We evaluated the density of myelinated axons within the main branch of the sciatic nerve, finding a significant reduction in Twitcher mice (TWI) mice compared with WT littermates (Fig. 1C)
Summary
Krabbe disease (KD)[1], known as globoid cell leukodistrophy, is a neurodegenerative disorder of the leukodistrophies family mainly affecting infancy-childhood and more rarely adulthood[2,3,4]. Combination of cell therapy with gene therapy[12,13,14], substrate reduction therapy[15], pharmacological chaperone therapy[16] and/or anti-oxidant therapy[17], has resulted in a synergic therapeutic effect These strategies just afforded a slowdown of KD progression and a limited lifespan extension, suggesting that other targets should be identified and treated. Recent studies proposed a dying-back mechanism for neuronal degeneration, independent of demyelination[7, 18]: Caspase[3] (an apoptosis signal) is increased in KD sciatic nerves compared with spinal cords[8]. Axonal loss in sciatic nerves occurs before apoptosis of cell bodies, even before clinical onset of KD symptoms[19] These findings represent an alternative to older theories of the dying-forward and demyelination-dependent progression for KD7, based on the analysis of peripheral nerves ultrastructure[10, 20]. Our data unveil possible novel mechanisms taking part into KD progression that should be taken into account in the search for new therapeutic approaches
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