No abstract

Alpha-synuclein (ASN) is a presynaptic protein that can easily change its conformation under different types of stress. It’s assumed that ASN plays an important role in the pathogenesis of Parkinson’s and Alzheimer’s disease. However, the molecular mechanism of ASN toxicity has not been elucidated. This study focused on the role of extracellular ASN (eASN) in regulation of transcription of sirtuins (Sirts) and DNA-bound poly(ADP-ribose) polymerases (PARPs) - proteins crucial for cells’ survival/death. Our results indicate that eASN enhanced the free radicals level, decreased mitochondria membrane potential, cells viability and activated cells’ death. Concomitantly eASN activated expression of antioxidative proteins (Sod2, Gpx4, Gadd45b) and DNA-bound Parp2 and Parp3. Moreover, eASN upregulated expression of Sirt3 and Sirt5, but downregulated of Sirt1, which plays an important role in cell metabolism including Aβ precursor protein (APP) processing. eASN downregulated gene expression of APP alpha secretase (Adam10) and metalloproteinases Mmp2, Mmp10 but upregulated Mmp11. Additionally, expression and activity of pro-survival sphingosine kinase 1 (Sphk1), Akt kinase and anti-apoptotic protein Bcl2 were inhibited. Moreover, higher expression of pro-apoptotic protein Bax and enhancement of apoptotic cells’ death were observed. Summarizing, eASN significantly modulates transcription of Sirts and enzymes involved in APP/Aβ metabolism and through these mechanisms eASN toxicity may be enhanced. The inhibition of Sphk1 and Akt by eASN may lead to disturbances of survival pathways. These results suggest that eASN through alteration of transcription and by inhibition of pro-survival kinases may play important pathogenic role in neurodegenerative disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-016-0317-1) contains supplementary material, which is available to authorized users.

Parkinson's disease (PD) is one of the most common serious neurodegenerative disorders in the world. The incidence of PD appears to be growing and this illness has an unknown pathogenesis. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra (SN), with an enigmatic cause in most individuals. Current pharmacotherapies and surgery provide symptomatic relief but their effects against the progressive degeneration of neuronal cells are strongly limited if present at all. Therefore, uncovering novel molecular mechanisms of DA cell death and new potentially disease-modifying pharmacological targets is an important task for basic research. Significant progress has been made in understanding the role of disturbed sphingolipid metabolism, particularly relating to ceramide and sphingosine-1-phosphate (S1P) in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative diseases. Additionally, the neuroprotective potential of an S1P receptors (S1PR) modulator, fingolimod (FTY720), in multiple sclerosis (MS) and numerous other diseases has been observed over the past decade. In this review, we briefly summarise recent achievements in defining intracellular S1PR-dependent actions, discuss their significance to therapeutic approaches, and explore their neuroprotective potential as a target in PD treatment.