Lysosphingolipids and sphingolipidoses: Psychosine in Krabbe's disease

Abstract

Until recently, lipids were considered inert building blocks of the cellular membranes. This changed three decades ago when lipids were found to regulate cell polarity and vesicle transport, and the “lipid raft” concept took shape. The lipid-driven membrane anisotropy in form of “rafts” that associate with proteins led to the view that organized complexes of lipids and proteins regulate various cell functions. Disturbance of this organization can lead to cellular, tissue, and organ malfunction. Sphingolipidoses, lysosomal storage diseases that are caused by enzyme deficiencies in the sphingolipid degradation pathway, were found to be particularly detrimental to the brain. These enzyme deficiencies result in accumulation of sphingolipid metabolites in lysosomes, although it is not yet clear how this accumulation affects the organization of lipids in cellular membranes. Krabbe disease or globoid cell leukodystrophy was one of the first sphingolipidosis for which the raft concept offered a potential mechanism. Krabbe disease is caused by mutations in the enzyme β-galactocerebrosidase, however, elevation of its substrate, galactosylceramide, is not observed or considered detrimental. Instead, it was found that a byproduct of galactosylceramide metabolism, the lysosphingolipid psychosine, is accumulated. The “psychosine hypothesis” has been refined by showing that psychosine disrupts “lipid rafts” and vesicular transport critical for the function of glia and neurons. The role of psychosine in Krabbe disease is an example of how the disruption of the sphingolipid metabolism can lead to elevation of a toxic lysosphingolipids resulting in disruption of cellular membrane organization and neurotoxicity.

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

“…In the last decades, "psychosine hypothesis" argued that the loss of GALC activity leads to a progressive accumulation of psychosine that, in turn, results in demyelination and cell death (Spassieva & Bieberich, 2016;Suzuki, 1998) In light of our results, we suggest that, at the early stage of the disease, ER stress together with the cytoskeleton damage determines a strong cellular impairment with the induction of a neuroinflammation. Therefore, even if further studies are needed, we may hypothesize that all these mechanisms can synergistically lead, in a brief time, to the fatal consequences of the disease, opening new perspectives on the pathogenesis of the disease.…”

“…In particular, psychosine, retained the main pathological cause of Krabbe disease (Igisu & Suzuki, 1984), preferentially accumulates in lipid raft (LR) domains disrupting their architecture and composition even at 3 days after birth (Taniike & Suzuki, 1994). Actually, this process causes an impairment in the activation of kinases and phosphatases, as suggested also by our REVIGO analysis, and in lipid metabolism or directly affects receptors and channels (Spassieva & Bieberich, 2016). Actually, this process causes an impairment in the activation of kinases and phosphatases, as suggested also by our REVIGO analysis, and in lipid metabolism or directly affects receptors and channels (Spassieva & Bieberich, 2016).…”

“…There are many evidences that psychosine accumulation leads to cellular and ER membrane LR disorganization (Cantuti Castelvetri et al, 2013). Actually, this process causes an impairment in the activation of kinases and phosphatases, as suggested also by our REVIGO analysis, and in lipid metabolism or directly affects receptors and channels (Spassieva & Bieberich, 2016). Of relevance, defects in LR determine protein kinase C misregulation that may cause defects in proliferation, differentiation, and apoptosis.…”

α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies

“…The first report of PD patients carrying allelic GALC mutations has been recently published 31 . Mutations in the GALC gene cause the toxic accumulation of psychosine in KD 32 – 37 . Psychosine, a GSL composed of a galactosyl sugar moiety bound to the sphingoid base sphingosine, is a potent inhibitor of several neuronal functions in KD 38 – 40 and facilitates the formation of insoluble α-synuclein aggregates in vitro 1 .…”

LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease

“…SL lacking the N- linked fatty acid and thus with a free amino group) of the primary stored compound has been reported in tissues from patients with many sphingolipidoses. Following the initial description of elevated galactosylsphingosine (psychosine) levels in Krabbe disease brain [ 9 , 10 ], LysoSLs have been considered as "toxic metabolites" contributing to the pathophysiology of several sphingolipidoses [ 11 – 15 ], and have been shown to play a variety of pathophysiological roles [ 16 , 17 ]. In recent years, owing to the development of tandem mass spectrometry (MS/MS), their measurement in biological fluids has become possible, and nearly each LysoSL has emerged as a sphingolipidosis biomarker [ 6 , 18 – 22 ].…”