Involvement of Lipids in the Pathogenesis of Amyotrophic Lateral Sclerosis.

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.

The Sphingolipid Asset Is Altered in the Nigrostriatal System of Mice Models of Parkinson's Disease.

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.