Bioactive lipids and their metabolism: New therapeutic opportunities for Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurological disorder characterized by motor dysfunction, which can also be associated with non‐motor symptoms. Its pathogenesis is thought to stem from a loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies containing aggregated α‐synuclein. Recent works suggested that lipids might play a pivotal role in the pathophysiology of PD. In particular, the so‐called ‘bioactive’ lipids whose changes in the concentration may lead to functional consequences and affect many pathophysiological processes, including neuroinflammation, are closely related to PD in terms of symptoms, disease progression and incidence. This study aimed to explore the molecular metabolism and physiological functions of bioactive lipids, such as fatty acids (mainly unsaturated fatty acids), eicosanoids, endocannabinoids, oxysterols, representative sphingolipids, diacylglycerols and lysophosphatidic acid, in the development of PD. The knowledge of bioactive lipids in PD gained through preclinical and clinical studies is expected to improve the understanding of disease pathogenesis and provide novel therapeutic avenues.

Comparative assessment of projection and clustering method combinations in the analysis of biomedical data

“…6). This agrees with published evidence that lipidomic regulation is supported by evidence for all three classes such as for sphingosine kinase 1 and sphingosine-1-phosphate [47], ceramides and glucosylceramide [48-51], phospholipids [52] and also for lysophosphatidic acids [53][54][55][56]. The isomap projection provided the best basis for a cluster structure that matched the prior class structure, followed by t-SNE, while the other projection methods performed clearly worse (Fig.…”

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

“…It has been shown that in a specific brain region of patients affected by severe PD, there was a significant increase in the expression of enzymes involved in Cer synthesis [ 93 ]. Moreover, Cer levels have been associated not only with the pathogenesis of PD but they have also been correlated with cognitive function [ 94 ].…”

“…On these bases, the inhibition of Cer signaling could be an important target for new therapies for PD. It has been shown that, in an in vitro PD model, SphKs and S1P lyase gene expression was significantly altered and that the cytosolic SphK1 and nuclear SphK2 activities were significantly reduced [ 94 , 96 , 97 , 98 ]. Several papers have shown that FTY720 prevented the loss of DA neurons in 6-hydroxydopamine-, rotenone- and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD cellular and animal models [ 99 , 100 , 101 , 102 ].…”

“…Pyszko and collaborators demonstrated that in in vitro experimental PD models, the inhibition of SphKs increases α-synuclein secretion, suppresses PI3K/Akt activation and activates the gene expression of pro-apoptotic proteins, strongly suggesting that SphK1 inhibition plays an important role in caspase-dependent apoptotic neuronal death [ 96 ]. Thus, SphKs/S1P/S1P receptor signalling has a crucial role in the pathogenesis of PD and could be a promising target to develop new therapies for PD [ 94 ]. It has been reported that in post-mortem brain tissues in PD patients Cer levels increase [ 17 ], but there are no significant data on S1P levels even if, in experimental disease models, reduced SphK activity has been demonstrated [ 96 ].…”

“…The findings that altered sphingolipid metabolism has a role in neurodegenerative diseases suggest that the modulation of sphingolipid metabolism might provide a useful strategy for treating these disorders [ 46 , 94 ]. Furthermore, ND are associated with mutations able to impair membrane trafficking between endosomes and the Golgi apparatus.…”