Abstract
Sphingolipids (SL) modulate several cellular processes including cell death, proliferation and autophagy. The conversion of sphingomyelin (SM) to ceramide and the balance between ceramide and sphingosine-1-phosphate (S1P), also known as the SL rheostat, have been associated with oxidative stress and neurodegeneration. Research in the last decade has focused on the possibility of targeting the SL metabolism as a therapeutic option; and SL levels in biofluids, including serum, plasma, and cerebrospinal fluid (CSF), have been measured in several neurodegenerative diseases with the aim of finding a diagnostic or prognostic marker. Previous reviews focused on results from diseases such as Alzheimer’s Disease (AD), evaluated total SL or species levels in human biofluids, post-mortem tissues and/or animal models. However, a comprehensive review of SL alterations comparing results from several neurodegenerative diseases is lacking. The present work compiles data from circulating sphingolipidomic studies and attempts to elucidate a possible connection between certain SL species and neurodegeneration processes. Furthermore, the effects of ceramide species according to their acyl-chain length in cellular pathways such as apoptosis and proliferation are discussed in order to understand the impact of the level alteration in specific species. Finally, enzymatic regulations and the possible influence of insulin resistance in the level alteration of SL are evaluated.
Highlights
Cell membranes are composed of several hundreds of different lipid species, having lipids and proteins more or less restricted movements as a consequence of interactions between them and cytoskeletal molecules [1]
Two species measured in more than one study were consistently found elevated in patients: HexCer d18:1/16:0 in Multiple Sclerosis (MS), Parkinson’s disease (PD) and age-related macular degeneration (AMD), and HexCer d18:1/18:1 in the same study that evaluated Alzheimer’s Disease (AD) and dementia with Lewy bodies (DLB) patients compared to controls (Table 2)
Our lipidomics study using serum samples of AMD and control subjects observed an increase in SM 42:2 and 42:3, possibly SM d18:1/24:1 and 24:2, in geographic atrophy (GA) patients compared to controls correction for multiple comparisons made the differences not significant [51]
Summary
Cell membranes are composed of several hundreds of different lipid species, having lipids and proteins more or less restricted movements as a consequence of interactions between them and cytoskeletal molecules [1]. SL are highly enriched in nervous cells and they exert specific roles in modulating cell signaling, controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and transmission, and neuron-glia interactions [7]. For this reason, the nervous system is vulnerable to SL storage disorders [8]. The importance of SL in regulating neuronal and glial survival has led researchers to investigate possible level alterations of SL in neurodegenerative diseases Biofluids such as plasma, serum, and to a lesser extent cerebrospinal fluid (CSF) are accessible sources of biomarkers, and they are chosen by researchers when investigating alterations of specific molecules in living patients with neurodegenerative diseases, including retina pathologies. The possible implication of the changes in SL species in processes associated with neurodegeneration, such as apoptosis, inflammation, and insulin resistance, are discussed, together with the potential utility of sphingolipidomic studies in basic and clinical research
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