Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

Abstract

Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5'-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)-a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity.

Keywords: S1P lyase (SPL); SPL inhibitors; neurodegeneration; neuroinflammation; sphingosine-1-phospahte (S1P).

Figure 1

Metabolism of sphingolipids. Abbreviations: CDase—ceramidase; Cer—ceramide; CerS—ceramide synthase; HE—hexadecenal; P-Etn—phosphoethanolamine; Sph—sphingosine; SphK1—sphingosine kinase 1; SphK2—sphingosine kinase 2; S1P—sphingosine-1-phosphate; SPL—sphingosine-1-phosphate lyase; S1PPs—sphingosine-1-phosphate phosphatases.

Figure 2

Changes in SPL and other S1P-metabolizing enzymes in neurodegenerative diseases—state-of-the-art data from patients and experimental models. Aβ—amyloid β peptide; AD—Alzheimer’s disease; ALS—amyotrophic lateral sclerosis; HD—Huntington’s disease; S1PP—sphingosine-1-phosphate phosphatase; PD—Parkinson’s disease; S1PP2—sphingosine-1-phosphate phosphatase 2; S1PR1—S1P receptor 1; SphK1—sphingosine kinase 1; SphK2—sphingosine kinase 2; SPL—sphingosine-1-phosphate lyase.