alpha-synuclein and sphingosine-1-phosphate

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.

Topics: alpha-Synuclein; Animals; Humans; Lysophospholipids; Molecular Targeted Therapy; Neuroprotection; Parkinson Disease; Signal Transduction; Sphingosine

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling. Treatment of human neuroblastoma cells with recombinant α-Syn caused S1P type 1 (S1P

Topics: alpha-Synuclein; beta-Arrestins; Cell Line, Tumor; Cell Movement; Fluorescence Resonance Energy Transfer; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Lysophospholipids; Mutation; Neurons; Platelet-Derived Growth Factor; Receptors, Lysosphingolipid; Recombinant Proteins; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine kinases (SphK 1&2) are involved in the regulation of cell survival, differentiation and neurotransmitter secretion. Current data suggest potential links between sphingolipid signalling, α-synuclein (ASN) and Alzheimer's disease (AD). Our aim was to investigate the possible role of SphKs and ASN in the regulation of the production and secretion of the amyloid β precursor protein (APP). We have previously shown that ASN intensified the secretion and toxicity of amyloid β (Aβ) to the point where it caused cell death. Our current results show that APP, the precursor protein for Aβ, is also influenced by ASN. The stable overexpression of wtASN in SH-SY5Y cells caused a three-fold, significant increase of the cellular APP level. This suggests that the influence of ASN on Aβ metabolism may actually occur at the level of APP protein rather than only through the changes of its cleavage into Aβ. To elucidate the mechanisms of APP modulation the cells were exposed to S1P and an SphK inhibitor (SKI). 72 h S1P treatment at 5 µM caused a nearly 50% reduction of the cellular APP signal. S1P also caused a tendency towards higher APP secretion, though the results were insignificant. The inhibition of SphKs decreased medium APP levels in a dose-dependent manner, reaching significance at 5 µM SKI with a correspondingly elevated intracellular level. Thus, it is reasonable to expect that in fact the influence of SphK activity on APP might be pro-secretory. This would also be in agreement with numerous articles on SphK-dependent secretion in the literature. The chronic nature of AD further suggests that subtle alterations in APP metabolism could have the potential to drive important changes in brain condition.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Blotting, Western; Cell Line, Tumor; Humans; Lysophospholipids; Neurons; Polymerase Chain Reaction; Sphingosine; Transfection