Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Abstract

Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside bgalactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose-and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.-Giri, S

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…Interestingly, in this current study, although psychosine alone had no effect on pro-inflammatory cytokine levels, it augmented the LPS-induced release of IL6 from mouse astrocytes, with a similar trend for the levels of TNFα and IL1β. This finding is comparable to those reported previously where psychosine potentiated LPS-induced production of TNFα, IL6, IL1β and NO in primary rat astrocytes, which in turn was suggested to induce oligodendrocyte cell death (Giri et al, , 2006. These enhanced levels of cytokines were reduced by pFTY720, in agreement with previous studies from our and other groups demonstrating that S1PRs play a role in regulating the levels of cytokines in a number of immune and glial cells (Choi et al, 2011;Sheridan and Dev, 2012;Wang et al, 2007;Zhang et al, 2008).…”

“…Inflammatory molecules, such as AMP-activated protein kinase (AMPK), prostaglandin D, inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines have all been implicated in Krabbe disease as well as in the twi/twi mouse animal model of this disease (Giri et al, 2008). Taken together, this increasing evidence now suggests that the loss of oligodendrocytes and widespread demyelination seen in Krabbe disease is due to apoptotic processes as well as aberrant inflammatory response (Giri et al, 2008(Giri et al, , 2006Haq et al, 2003;Tohyama et al, 2001).…”

Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease

“…Thus, abnormal sphingolipid catabolism or accumulation in lipid microdomains might result in a cell autonomous defect accounting for GLD hematopoietic stem cells compromised functionality (i.e., proliferation, migration, and maturation). Furthermore, because psychosine directly deregulates some specific protein kinase C isozymes (Hannun and Bell, 1987), activates phospholipase A2 (Giri et al, 2006), and modifies mitochondrial membrane potential (Tapasi, 1998) and peroxisomal activity (Khan et al, 2005), its accumulation within thymic stromal tissue or in T cells might also directly interfere with cell survival. Of note, a recent study reported that psychosine favors proinflammatory cytokine secretion by peripheral blood mononuclear cells derived from Krabbe patients (Formichi et al, 2007;Pasqui et al, 2007).…”

Intracellular delivery and sensing based on polyelectrolyte multilayer capsules

“…The lack of insulation leads to slower signaling which can be measured in a nerve conduction study [101]. A simple model of Krabbe disease can be obtained from the MO3.13 cell line [102,103]. These cells are immortalized oligodendrocytes.…”