Lipids in Neurodegenerative Diseases

Lipids are undoubtedly the major constituents of the cell membranes of all living organisms, and the most efficient source of energy [1]. However, they also act as intercellular and intracellular signaling mediators by exerting many cell functions upon binding to specific G protein-coupled receptors and by interacting with them, thus modulating their localization and activation. Their ability to act as signaling mediators has earned them the name “bioactive lipids” [2]; said bioactive lipids are divided into four main families: classical eicosanoids, glycerophospholipids and sphingolipids, specialized pro-resolving lipid mediators, and endocannabinoids [3,4]. Although many neurodegenerative diseases are characterized by abnormal protein aggregates, with each pathologic aggregate having a distinctive temporo-spatial pattern of spread throughout the nervous system that is characteristic of a specific disorder, increasing evidence suggests that lipid membrane composition and the alteration of lipid metabolism play a major role in the propagation of neurodegeneration-associated protein aggregates throughout the brain [5]. In fact, we hinted at the multifaceted role that lipids have in pathophysiological cascades, which then lead to the most common (and, indeed, to the less common) neurodegenerative diseases, in the Editorial preceding this Special Issue “Lipids in Neurodegenerative diseases”, within the International Journal of Molecular Sciences. This valuable contribution to the field is made up of eight papers: five original articles and three reviews, providing new information about several classes of lipids under both normal and pathological conditions. In their review, Mandik and Vos [6] argue that despite it being well established that many neurodegenerative diseases are characterized by protein deposits, sphingolipids also take center stage in their underlying pathogenesis. The authors particularly focused on Parkinson’s disease (PD) and neurodegeneration with brain iron accumulation (NBIA), all characterized by extrapyramidal symptoms coupled to cognitive impairment and psychiatric disturbance [7]. The accumulation of subclasses of sphingolipids or of their byproducts (as well as defects in their metabolism) is typical of PD and NBIA with genetic mutations. The authors suggest not only that sphingolipid metabolism may be an interesting therapeutic target for these diseases, but also that a diet controlling the specific affected sphingolipids might provide a beneficial effect to patients. Among the classes of sphingolipids, glycosphingolipids, which are all derived from lactosylceramide (LacCer) and include gangliosides, play key pathophysiological roles in vastly different processes including development, neuronal differentiation, and modulating receptor signaling [8]. Accordingly, Dei Cas et al. [9] developed a very accurate and sensitive novel approach to measure LacCer synthase activity in vitro using deuterated glucosylceramide via liquid chromatography coupled with tandem mass spectrometry; this method has the advantage of avoiding the costs and discomforts of managing radiochemicals. On the other hand, one of the main gangliosides, GM1, which is particularly expressed in the central nervous system, was shown to interact and form a stable complex with GPR37 in the article by Hertz et al. [10]. The authors showed the GPR37-dependent rescue effect of GM1 against