title: Biochemical, cell biological, pathological, and therapeutic aspects of Krabbe's disease.
abstract: Krabbe's disease (KD; also called globoid cell leukodystrophy) is a genetic disorder involving demyelination of the central (CNS) and peripheral (PNS) nervous systems. The disease may be subdivided into three types, an infantile form, which is the most common and severe; a juvenile form; and a rare adult form. KD is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase activity in lysosomes, leading to accumulation of galactoceramide and neurotoxic galactosylsphingosine (psychosine [PSY]) in macrophages (globoid cells) as well as neural cells, especially in oligodendrocytes and Schwann cells. This ultimately results in damage to myelin in both CNS and PNS with associated morbidity and mortality. Accumulation of PSY, a lysolipid with detergent-like properties, over a threshold level could trigger membrane destabilization, leading to cell lysis. Moreover, subthreshold concentrations of PSY trigger cell signaling pathways that induce oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, endothelial/vascular dysfunctions, and neuronal and axonal damage. From the time the "psychosine hypothesis" was proposed, considerable efforts have been made in search of an effective therapy for lowering PSY load with pharmacological, gene, and stem cell approaches to attenuate PSY-induced neurotoxicity. This Review focuses on the recent advances and prospective research for understanding disease mechanisms and therapeutic approaches for KD. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Je-Seong
authors.initials: JS
authors.lastname: Won
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.|Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina.
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina. singhi@musc.edu.
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D003711:Demyelinating Diseases; D005698:Galactosylceramidase / Q000172:deficiency; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000145:classification / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D008247:Lysosomes / Q000201:enzymology; D009420:Nervous System / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011609:Psychosine / Q000378:metabolism
chemical_list: D011609:Psychosine; D005698:Galactosylceramidase
keywords: Krabbe's disease; globoid cell leukodystrophy; myelin; therapy