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.

The aim of this study was to evaluate changes in the content of sphingoid bases - sphingosine (SPH), sphinga-nine, and sphingosine-1-phosphate (SPH-1-P) - and in expression of genes encoding enzymes...

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.

Glucan linked to proteins is a natural mega-glycoconjugate (mGC) playing the central role as a structural component of a yeast cell wall (CW). Regulation of functioning of non-covalently bound glucanosyltransglycosylases (ncGTGs) that have to remodel mGC to provide CW extension is poorly understood. We demonstrate that the main ncGTGs Bgl2 and Scw4 have phosphorylated and glutathionylated residues and are represented in CW as different pools of molecules having various firmness of attachment. Identified pools contain Bgl2 molecules with unmodified peptides, but differ from each other in the presence and combination of modified ones, as well as in the presence or absence of other CW proteins. Correlation of Bgl2 distribution among pools and its N-glycosylation was not found. Glutathione affects Bgl2 conformation, probably resulting in the mode of its attachment and enzymatic activity. Bgl2 from the pool of unmodified and monophosphorylated molecules demonstrates the ability to fibrillate after isolation from CW. Revealing of Bgl2 microcompartments and their mosaic arrangement summarized with the results obtained give the evidence that the functioning of ncGTGs in CW can be controlled by reversible post-translational modifications and facilitated due to their compact localization. The hypothetical scheme of distribution of Bgl2 inside CW is represented.

—It was shown that sphingolipids are necessary for the normal functioning of neurons, and disturbance of their metabolism accompanies the development of brain diseases, including Parkinson’s disease (PD). Since the possibilities for studying the role of sphingolipids in the pathogenesis of PD in patients are extremely limited, experimental models must be used to solve this problem. Thus, in this work, using chromatography-mass spectrometry, the content of key molecular species of sphingolipids, total ceramides, hexosylceramides, and their derivatives, sphingosine and sphinganine, with proapoptotic properties in mice were studied using a model of the clinical stage of PD for the first time. This model was obtained by systemically administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which in the brain turns into MPP +, a toxin for catecholaminergic neurons. In the control, instead of MPTP, 0.9% NaCl was injected. It was shown that the total concentration of all studied sphingolipids increases in the substantia nigra, the location of dopaminergic neuron bodies, compared to the control. This occurred due to an increase in the concentration of ceramides associated with fatty acids, such as C18:1/14:0, C18:1/18:0, C18:1/24:1, and monohexosylceramides associated with fatty acids such as C18:1/18:0 and C18:1/24:1. Unlike the substantia nigra, the striatum, the site of projection of dopaminergic axons, had no changes in the content of sphingolipids. These data indicate that the death of nigrostriatal dopaminergic neurons in the PD model is accompanied by a change in the metabolism of sphingolipids, which opens up new possibilities for studying their role in the pathogenesis of this disease and in the search for a new class of drugs that correct sphingolipid metabolism.

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.