Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 139, Issue -, Pages 46-54Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2019.05.014
Keywords
Adrenic acid; Isoprostanes; Krabbe disease; Leukodystrophy; Murine models; Neuroprostanes; Oxidative stress
Funding
- Italian Association for Leucodistrophy of Krabbe Progetto Grazia
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Krabbe disease (KD) is a rare and devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. The disease leads to impaired myelin formation and extensive myelin damage in the brain. Oxidative stress is implicated in the pathogenesis of KD but insofar few information is available. The gray and white matter of the brain are rich in docosahexaenoic acid and adrenic acid respectively and under non-enzymatic oxidative stress, release isoprostanoids, i.e. F-4-neuroprostanes (F-4-NeuroPs) and F-2-dihomo-isoprostanes (F-2-dihomo-IsoPs). In this study, the formation of isoprostanoids in brain tissue was investigated in a well-established KD mouse model (twitcher) that recapitulates the human pathology. According to the genotype determinations, three groups of mice were selected: wild-type control mice (n= 13), heterozygotes mice (carriers of GALC mutations, n= 14) and homozygous twitcher mice (n= 13). Measurement of F-2-dihomo-IsoP and F-4-NeuroP levels were performed on whole brain tissue obtained at day 15 and day 35 of the life cycle. Brain isoprostanoid levels were significantly higher in the twitcher mice compared to the heterozygous and wild-type control mice. However, F-2-dihomo-IsoP and F-4-NeuroP levels did not differ in brain of day 15 compared to day 35 of the heterozygote mice. Interestingly, isoprostanoid levels were proportionally enhanced with disease severity (F-2-dihomo-IsoPs, rho = 0.54; F-4-NeuroPs, rho = 0.581; P values <= 0.05; n= 13). Our findings are the first to show the key role of polyunsaturated fatty acid oxidative damage to brain grey and white matter in the pathogenesis and progression of KD. This shed new insights on the biochemical indexes of KD progression, and potentially provide information for novel therapeutic targets.
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