Parkinson’s disease (PD) is a neurodegenerative disease incurable due to late diagnosis and treatment. Therefore, one of the priorities of neurology is to study the mechanisms of PD pathogenesis at the preclinical and early clinical stages. Given the important role of sphingolipids in the pathogenesis of neurodegenerative diseases, we aimed to analyze the gene expression of key sphingolipid metabolism enzymes (ASAH1, ASAH2, CERS1, CERS3, CERS5, GBA1, SMPD1, SMPD2, UGCG) and the content of 32 sphingolipids (subspecies of ceramides, sphingomyelins, monohexosylceramides and sphinganine, sphingosine, and sphingosine-1-phosphate) in the nigrostriatal system in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of the preclinical and clinical stages of PD. It has been shown that in PD models, the expression of five of the nine studied genes (CERS1, CERS5, ASAH1, ASAH2, and GBA1) increases but only in the substantia nigra (SN) containing dopaminergic cell bodies. Changes in the expression of enzyme genes were accompanied by an increase in the content of 7 of the 32 studied sphingolipids. Such findings suggest these genes as attractive candidates for diagnostic purposes for preclinical and clinical stages of PD.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. To study its underlying mechanisms, a variety of models are currently used at the cellular level and in animals with mutations in multiple ALS associated genes, including SOD1, C9ORF72, TDP-43, and FUS. Key mechanisms involved in the disease include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammatory, and immune reactions. In addition, significant metabolism alterations of various lipids classes, including phospholipids, fatty acids, sphingolipids, and others have been increasingly recognized. Recently, the mechanisms of programmed cell death (apoptosis), which may be responsible for the degeneration of motor neurons observed in the disease, have been intensively studied. In this context, sphingolipids, which are the most important sources of secondary messengers transmitting signals for cell proliferation, differentiation, and apoptosis, are gaining increasing attention in the context of ALS pathogenesis given their role in the development of neuroinflammatory and immune responses. This review describes changes in lipids content and activity of enzymes involved in their metabolism in ALS, both summarizing current evidence from animal models and clinical studies and discussing the potential of new drugs among modulators of lipid metabolism enzymes.

Changes in the expression of genes for enzymes of sphingolipid metabolism in transgenic FUS mice (FUS (1-359)) simulating amyotrophic lateral sclerosis (ALS) were found. The profiles of molecular species of sphingomyelins (SM) and ceramides (CER) in the structure of the brain and in the spinal cord were analyzed. During the development of ALS, changes in the spectrum of molecular types of CER were noted only in the spinal cord, where almost all CER decreased in relation to the control after two and three months of the course of the disease. After four months of the development of the pathology, an increase in the expression of the acid ceramidase gene was observed, as a result of which sphingosine can be formed, which has pronounced proapoptotic properties. Analysis of gene expression of CER and galactosylceramide (GalCER) metabolism enzymes indicates the possibility of GalCER functioning as a source for maintaining CER levels at the terminal stage of ALS. Thus, the metabolism of sphingolipids is a promising field of study of the processes associated with ALS, both in the context of the search for potential diagnostic markers and effective drugs, and for explaining the pathogenesis of ALS.

Background: The aim of our study was to determine the role of sphingolipids, which control proliferation and apoptosis, in the placenta of pregnant women with pregnancy-associated breast cancer (PABC) after chemotherapy compared with healthy patients. Methods: We analyzed (by the PCR method) the gene expression of key sphingolipid metabolism enzymes (sphingomyelinases (SMPD1 and SMPD3), acid ceramidase (ASAH1), ceramide synthases (CERS 1–6), sphingosine kinase1 (SPHK1), sphingosine-1-phosphate lyase 1 (SGPL1), and sphingosine-1-phosphate receptors (S1PR1, S1PR2, and S1PR3)) and the content of subspecies of ceramides, sphingosine, and sphingosine-1-phosphate in seven patients with PABC after chemotherapy and eight healthy pregnant women as a control group. Results: We found a significant increase in the expression of genes of acid ceramidase (ASAH1), sphingosine-1-phosphate lyase 1 (SGPL1), sphingosine kinase (SPHK1), and ceramide synthases (CERS 1-3, 5, 6) in the samples of patients with PABC during their treatment with cytostatic chemotherapy. The increase in the expression of the enzymes’ genes was not accompanied by changes in the content of the studied sphingolipids. Such significant changes in the expression of genes controlling the level of CER, sphingosine, and S1P may indicate their ability to initiate the metabolism of pro-apoptotic and anti-apoptotic sphingolipids in the placenta of pregnant women with cancer undergoing chemotherapy in order to maintain levels typical of the placenta of healthy women. Conclusions: Our results may indicate the promising mechanism of placenta protection during chemotherapy for pregnant women with breast cancer and, consequently, of the newborn. This protective effect of the placenta and especially for the newborn has been discovered for the first time and requires more careful study.

This review highlights the main aspects of the involvement of sphingosine-1-phosphate (S1P) metabolism in the reparative processes of the adult brain, including neurogenesis, oligodendrogenesis and angiogenesis, which are necessary for the normal functioning of the central nervous system. Neurogenesis is a complex, multifactorial, and multi-stage process of formation of neurons and neuroglial cells from neural stem cells. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and fibroblast growth factor (FGF), play a special role in the regulation of neurogenesis. The fine regulation of neurogenesis, which occurs at all its stages, includes the molecular mechanisms of cellular signaling mediated by S1P and its receptors. In particular, S1P and its receptors affect adult neurogenesis at multiple stages: activation of S1P receptors induces neuroblast proliferation, migration, and morphological changes. Special attention is paid to the interaction of S1P and its receptors with the cellular environment (astrocytes, endothelial cells, and ependyma) of the neurogenic niche and the relationship between S1P metabolism and the expression of neurotrophins, which suggests a key role of S1P in regulating the environment of the neurogenic niche.