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Review

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

1
Department of Hybrid Microbiosystems Engineering, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Ks. Trojdena 4 St., 02-109 Warsaw, Poland
2
Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland
3
Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: José Luis Zugaza
Int. J. Mol. Sci. 2021, 22(12), 6277; https://doi.org/10.3390/ijms22126277
Received: 28 April 2021 / Revised: 1 June 2021 / Accepted: 2 June 2021 / Published: 11 June 2021
(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)
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. View Full-Text
Keywords: alpha-synuclein; sphingosine-1-phosphate; sphingosine-1-phosphate receptors; sphingosine kinases; Parkinson’s disease alpha-synuclein; sphingosine-1-phosphate; sphingosine-1-phosphate receptors; sphingosine kinases; Parkinson’s disease
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MDPI and ACS Style

Motyl, J.A.; Strosznajder, J.B.; Wencel, A.; Strosznajder, R.P. Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 6277. https://doi.org/10.3390/ijms22126277

AMA Style

Motyl JA, Strosznajder JB, Wencel A, Strosznajder RP. Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease. International Journal of Molecular Sciences. 2021; 22(12):6277. https://doi.org/10.3390/ijms22126277

Chicago/Turabian Style

Motyl, Joanna A., Joanna B. Strosznajder, Agnieszka Wencel, and Robert P. Strosznajder. 2021. "Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease" International Journal of Molecular Sciences 22, no. 12: 6277. https://doi.org/10.3390/ijms22126277

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