Krabbe's leukodystrophy: Approaches and models in vitro

Abstract

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.

RETRACTED: Blue Light Induces Down-Regulation of Aquaporin 1, 3, and 9 in Human Keratinocytes

“…AQPs were identified in the major systems of the human body such as nervous, renal, cardiovascular, respiratory, reproductive, digestive, musculoskeletal, and integumentary [ 11 ]. An extensive set of studies examined the physiological and pathological role of AQPs in fluid absorption and secretion, cell signaling transduction, cell metabolism, cell migration, cell proliferation [ 12 , 13 , 14 ], stem cell differentiation [ 15 , 16 ], and primary or secondary neurodegeneration with the concomitance of different degree of inflammation [ 17 , 18 ]. In the skin, AQPs permit rapid, regulated, and selective water permeability playing a role in skin hydration, cell proliferation, migration, immunity, and wound healing [ 19 ].…”

Increased isoprostanoid levels in brain from murine model of Krabbe disease – Relevance of isoprostanes, dihomo-isoprostanes and neuroprostanes to disease severity

“…Furthermore, increased amounts in unmetabolized galactocerebroside have been proposed to be cytotoxic to oligodendrocytes, which are the myelin-producing cells of the central nervous system [3,4]. Nevertheless, the exact mechanism of such cytotoxicity has not yet been fully elucidated but latest report suggests to take part in activating the immune system and neuroinflammation [5].…”

Identifying altered developmental pathways in human globoid cell leukodystrophy iPSCs-derived NSCs using transcriptome profiling

“…Small and large animal models of GLD have been widely used to study primary and secondary pathological events and to test new therapies [ 10 – 15 ]. Although the biochemical and histological features of these animal models are similar to those of human patients with GLD and partially recapitulate the spectrum of pathological manifestations observed in patients, large differences among species make it difficult for animal models to accurately reflect the clinical pathophysiology of humans, which increases the difficulty of extending the efficacy and toxicity of test results of potential drugs from animals to humans [ 16 ].…”

“…Although the biochemical and histological features of these animal models are similar to those of human patients with GLD and partially recapitulate the spectrum of pathological manifestations observed in patients, large differences among species make it difficult for animal models to accurately reflect the clinical pathophysiology of humans, which increases the difficulty of extending the efficacy and toxicity of test results of potential drugs from animals to humans [ 16 ]. In addition, human cell models of GLD include patient-specific fibroblasts, hematopoietic cells, or epithelial cell lines with GALC mutations, which poorly recapitulate the metabolic and functional characteristics of neural cells [ 10 ].…”