Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

Abstract

Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.

Altered Sphingolipid Hydrolase Activities and Alpha-Synuclein Level in Late-Onset Schizophrenia

“…Previously, decreased GCase activity was demonstrated in blood and brain samples of PD and DLB patients compared to controls [ 15 , 56 ], and at the same time, we and other researchers did not reveal a decrease in GCase activity in blood samples of PD patients [ 20 , 57 ]. Nevertheless, in the current study, increased HexSph concentration, which is a substrate of GCase, was found in late-onset SCZ patients compared to sPD patients and controls which supports the data about the role of ceramide metabolism in SCZ pathogenesis ( Figure 2 ) [ 58 ]. Our data support the role of ceramide metabolism in SCZ pathogenesis.…”

Stable and efficient expression of brain-derived neurotrophic factor in tobacco chloroplasts

“…The secreted BDNF enables to mediate multiple processes in the mammalian brain including sleep deprivation, memory, mode disorder, neuronal differentiation and growth, synapse formation, and plasticity [11,[37][38][39]. Due to the multiple physiological functions of BDNF in the healthcare industry such as Parkinson's disease [40,41], the growing supply-demand gap will be a great challenge for the scientists to fill in and the PMPs will be the batter option. For the plant-based expression system, chloroplast transformation has emerged as a new alternative to generate transplastomic plants due to some attractive features over nuclear transformation.…”

The Disease Modification Conundrum in Parkinson’s Disease: Failures and Hopes

“…But this simplification to create “pure” models may then undermine how preclinical models accurately represent their respective human condition. For example, cross-seeding in multiple proteinopathies is a recognized phenomenon in parkinsonian disorders ( Williams et al, 2020 ) and the interplay with other pathologies outside of proteinopathies is also known ( Motyl et al, 2021 ).…”