Ceramide and neurodegeneration: Susceptibility of neurons and oligodendrocytes to cell damage and death

Abstract

Neurodegenerative disorders are marked by extensive neuronal apoptosis and gliosis. Although several apoptosis-inducing agents have been described, understanding of the regulatory mechanisms underlying modes of cell death is incomplete. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received worldwide attention in recent years. The SM pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and on downstream targets. Sphingomyelin, a plasma membrane constituent, is abundant in mammalian nervous system, and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Neutral sphingomyelinase (NSMase) is a key enzyme in the regulated activation of the SM cycle and is particularly sensitive to oxidative stress. In a context of increasing clarification of the mechanisms of neurodegeneration, we thought that it would be useful to review details of recent findings that we and others have made concerning different pro-apoptotic neurotoxins including proinflammatory cytokines, hypoxia-induced SM hydrolysis and ceramide production that induce cell death in human primary neurons and primary oligodendrocytes: redox sensitive events. What has and is emerging is a vista of therapeutically important ceramide regulation affecting a variety of different neurodegenerative and neuroinflammatory disorders.

Regulating survival and development in the retina: key roles for simple sphingolipids

“…Cer has a central role in sphingolipid metabolism and plays many relevant physiological functions ( 6,7,(19)(20)(21)(22). This demands keeping a tight control of its cellular level; hence, the routes for Cer generation and removal respond to a variety of cell stimuli that control the activities of at least 26 different enzymes in diverse intracellular locations ( 6,23,24 ).…”

“…The choice among the diverse intracellular pathways and biological outcomes activated by Cer depends on its levels, the molecular species formed, the cell type and age, the subcellular localization, the expression of specifi c receptors, and the selective targets coupled to specifi c signaling pathways ( 22 ). Cer differentially modifi es the activity of a large number of intracellular effectors ( 31,34 ) ( Fig.…”

“…mer's disease and recent data involves Cer in amyloid ␤ peptide generation ( 22 ). Hence, understanding the signaling pathways activated by Cer to induce neuronal death might provide clues for treating neurodegenerative diseases.…”

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

“…Endogenous cellular levels of ceramide increase after stimulation with different proapoptotic factors that cause acute and chronic disease (10,11). This increase in ceramide can originate from an activation of de novo biosynthesis, a rise in ceramide hydrolysis from sphingomyelin by the action of neutral or acid sphingomyelinases, or a decrease in ceramide metabolism due to glycosylation, phosphorylation, or deacetylation (12).…”

“…This increase in ceramide can originate from an activation of de novo biosynthesis, a rise in ceramide hydrolysis from sphingomyelin by the action of neutral or acid sphingomyelinases, or a decrease in ceramide metabolism due to glycosylation, phosphorylation, or deacetylation (12). An important role for ceramide-mediated apoptosis in neurodegenerative and neuroinflammatory diseases has now been established (10).…”