Krabbe's leukodystrophy: Approaches and models in vitro.

This Review describes some in vitro approaches used to investigate the mechanisms involved in Krabbe's disease, with particular regard to the cellular systems employed to study processes of inflammation, apoptosis, and angiogenesis. The aim was to update the knowledge on the results obtained from in vitro models of this neurodegenerative disorder and provide stimuli for future research. For a long time, the nonavailability of established neural cells has limited the understanding of neuropathogenic mechanisms in Krabbe's leukodystrophy. More recently, the development of new Krabbe's disease cell models has allowed the identification of neurologically relevant pathogenic cascades, including the major role of elevated psychosine levels. Thus, direct and/or indirect roles of psychosine in the release of cytokines, reactive oxygen species, and nitric oxide and in the activation of kinases, caspases, and angiogenic factors results should be clearer. In parallel, it is now understood that the presence of globoid cells precedes oligodendrocyte apoptosis and demyelination. The information described here will help to continue the research on Krabbe's leukodystrophy and on potential new therapeutic approaches for this disease that even today, despite numerous attempts, is without cure. © 2016 Wiley Periodicals, Inc.

A galactose-free diet enriched in soy isoflavones and antioxidants results in delayed onset of symptoms of Krabbe disease in twitcher mice.

Krabbe disease or globoid cell leukodystrophy is an autosomal recessively inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme that catalyzes the hydrolysis of galactose from galactosylceramide and galactosylsphingosine (psychosine). Psychosine accumulation results in the loss of myelin and oligodendrocytes in the brain of Krabbe patients as well as twitcher mice (natural model of human Krabbe disease). The aim of the present research was to investigate in twitcher mice the potential role of a diet deficient in galactose enriched in soy isoflavones and a pool of antioxidants molecules, such as l-glutathione, coenzyme Q10, xanthophylls, in counteracting the toxic effects derived by psychosine accumulation. A second goal of this manuscript was to demonstrate suppression of the apoptotic effects of psychosine in cultured oligodendrocyte progenitor mice cells (OLP-II) with antioxidants. The affected twitcher mice began the milk-derivatives free diet on post-natal day 15 although they also received mother's milk until post-natal day 18. Nevertheless, average life span was increased 50%, from 32+/-2 to 48+/-3 days, onset of tremor was delayed 17 days (from 21 days in the untreated twitcher mice to 38 days in the treated affected mice) and the gait in the treated mice was normal until almost a week after the untreated animals died (38+/-1 days versus 32 days at death). Weight gain in the treated animals also progressed to 38 days compared with 22 days for the untreated affected twitcher mice. Protection of the OLP-II cells against psychosine was shown using the MTT test (the ability of the tetrazolium salt MTT to form a dark blue formazan product by mitochondrial dehydrogenase in viable cells) and assay of expression of p53 and TNF-related apoptosis-inducing ligand (TRAIL). The results showed a time-dependent and concentration-dependent decrease of OLP-II viability on exposure to psychosine and dose-dependent protection with the antioxidants xanthophylls and glutathione. They also demonstrated that psychosine-induced p53 induction of apoptosis and TNF-related apoptosis-inducing ligand receptors could be decreased by l-glutathione and xanthophylls. A dietary approach may constitute a promising clinical management of the late-infantile and juvenile forms of Krabbe leukodystrophy.