Exploring Sphingolipid Implications in Neurodegeneration

Abstract

Over the past decade, it was found that relatively simple sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate, and glucosylceramide play important roles in neuronal functions by regulating rates of neuronal growth and differentiation. Homeostasis of membrane sphingolipids in neurons and myelin is essential to prevent the loss of synaptic plasticity, cell death and neurodegeneration. In our review we summarize data about significant brain cell alterations of sphingolipids in different neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Amyotrophic Lateral Sclerosis, Gaucher's, Farber's diseases, etc. We reported results obtained in brain tissue from both animals in which diseases were induced and humans in autopsy samples. Moreover, attention was paid on sphingolipids in biofluids, liquor and blood, from patients. In Alzheimer's disease sphingolipids are involved in the processing and aggregation of β-amyloid and in the transmission of the cytotoxic signal β-amyloid and TNFα-induced. Recently, the gangliosides metabolism in transgenic animals and the relationship between blood sphingolipids changes and cognitive impairment in Alzheimer's disease patients have been intensively studied. Numerous experiments have highlighted the involvement of ceramide and monohexosylceramide metabolism in the pathophysiology of the sporadic forms of Parkinson's disease. Moreover, gene mutations of the glucocerebrosidase enzyme were considered as responsible for Parkinson's disease via transition of the monomeric form of α-synuclein to an oligomeric, aggregated toxic form. Disturbances in the metabolism of ceramides were also associated with the appearance of Lewy's bodies. Changes in sphingolipid metabolism were found as a manifestation of Amyotrophic Lateral Sclerosis, both sporadic and family forms, and affected the rate of disease development. Currently, fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator, is the only drug undergoing clinical trials of phase II safety for the treatment of Amyotrophic Lateral Sclerosis. The use of sphingolipids as new diagnostic markers and as targets for innovative therapeutic strategies in different neurodegenerative disorders has been included.

Keywords: brain; diagnostic marker; neurodegeneration; sphingolipids; therapeutic target.

Figure 1

The main sphingolipids (SphLs) and metabolism SphL enzymes in neurodegeneration. Above, the cell membrane, on the right the lysosome. Sphingomyelinase (SMase) degrades sphingomyelin (SM) to ceramide (Cer) and it is catabolized by ceramidase (Cerase) to sphingosine (Sph) that is utilized to form sphingosine-1-phosphate (S1P) by sphingosine kinase (SphK) and gangliosides (GMs). Cer is also used to form glucosylceramide (GCer) by glucosylceramide synthase (GCerS) and galactosylceramide (GalCer). GCer is degraded by glucocerebrosidases (GBA) and GalCer by galactosylceramidase (GalCerase). Also precursors of Cer as sphinganin (Sphn), sphingosine (Sph) and dihydroceramide (DHCer) are present in the brain as well dihydrosphingomyelin (DHSM).

Figure 2

Scheme of the sphingolipid involvement in Alzheimer's Disease. Glycosphingolipids (GSphLs), ganglioside 1 (GM1), sphingolipids (SphLs) are involved in the formation of Aβ aggregates. Aggregates stimulate nitric oxide that induces activation of both acid sphingomyelinase (aSMase) and neutral sphingomyelinase (nSMase). The increase of aSMase activity is responsible for ceramide (Cer) production in lysosomes that induces neuron apoptosis. The increase of nSMase activity produces cell membrane Cer that either is able to stimulate the synthesis of inflammatory cytokines with consequent astroglia activation or is catabolized to sphingosine (Sph). The sphingosine kinase is inhibited and therefore sphingosine-1-phospahte (S1P) level is very low. Both the accumulation of Sph and the reduction of S1P are responsible for neuron apoptosis.

Figure 3

Scheme of the sphingolipid involvement in Parkinson's Disease. Acid sphingomyelinase (aSMase) and acid ceramidase (aCerase), by producing ceramide (Cer) and sphingosine (Sph), respectively in lysosomes, are responsible for the reduction of α-synuclein production and aggregation. The inhibition of sphingosine kinase (SphK) reduces sphingosine-1-phospahte (S1P) level with consequent increase of α-synuclein. Mutation of the GBA gene encoding the glucocerebrosidase enzyme induce accumulation of glucosylceramide (GCer) that induces α-synuclein increase.

Figure 4

Scheme of the sphingolipid involvement in Amyotrophic Lateral Sclerosis. The ceramide (Cer) is the most important sphingolipid in Amyotrophic Lateral Sclerosis. It is produced by glucocerebrosidase (GCBase), galactosylceramidase (GalCerase), sphingomyelinase (SMase) and it is used by glucosylceramide synthase (GCerS), acid ceramidase (aCerase), lactosylceramide synthase (LacCerS), ganglioside synthase (GMS) to form glucosylceramide (GCer), sphingosine (Sph), lactosylceramide (LacCer), ganglioside (GM), respectively. These molecules are all involved in apoptosis that occurs in disease.