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Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

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Review

Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

Alba Di Pardo et al. Front Neurosci.

Abstract

Neurodegenerative diseases represent a class of fatal brain disorders for which the number of effective therapeutic options remains limited with only symptomatic treatment accessible. Multiple studies show that defects in sphingolipid pathways are shared among different brain disorders including neurodegenerative diseases and may contribute to their complex pathogenesis. In this mini review, we discuss the hypothesis that modulation of sphingolipid metabolism and their related signaling pathways may represent a potential therapeutic approach for those devastating conditions. The plausible "druggability" of sphingolipid pathways is greatly promising and represent a relevant feature that brings real advantage to the development of new therapeutic options for these conditions. Indeed, several molecules that selectively target sphingolipds are already available and many of them currently in clinical trial for human diseases. A deeper understanding of the "sphingolipid scenario" in neurodegenerative disorders would certainly enhance therapeutic perspectives for these conditions, by taking advantage from the already available molecules and by promoting the development of new ones.

Keywords: FTY720; S1P; S1PRs; ceramide; neurodegenerative diseases; sphingolipid metabolism.

Figures

Figure 1
Figure 1
Simplified schematic representation of sphingolipid biosynthesis. Serine palmitoyltransferase (SPT) catalyzes the initial reaction of the de novo biosynthesis of sphingolipids. Dihydrosphingosine (dhSPH) is generated after an intermediate step by the action of 3-keto-dihydrosphingosine reductase (KDS). Successively, dhSph can be either phosphorylated, with the generation of dhSphingosine-1-phosphate by sphingosine kinases (SPHKs), or acetylated by ceramide synthase (CERS) and desaturated by ceramide desaturase (DES) to form ceramide. Ceramide may also derive from the Salvage pathway through either the hydrolysis of sphingomyelin or by the recycling of gangliosides by Sphingomyelin Phosphodiesterase (SMPD) and Glucosylceramidase (GBA) respectively. Ceramide can be phosphorylated by Ceramide kinase (CerK) with the generation of ceramide-1-phosphate (C1P) which in turn can be re-converted in ceramide by Lipid Phosphate Phosphatases (LPPs). Ceramide can be subsequently metabolized by Ceramidase (CDase) to generate sphingosine which, in turn, produces sphingosine-1-phosphate (S1P) through phosphorylation by SPHKs. S1P can be either dephosphorylated and re-converted to sphingosine by S1P Phosphatases (SPPs), or irreversible catabolized into hexadecenal + phospho-ethanolamine by S1P Lyase (SGPL1).

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