Alpha-synuclein alters differently gene expression of Sirts, PARPs and other stress response proteins: implications for neurodegenerative disorders

J Motyl,M Cieślik,R P Strosznajder,J B Strosznajder,P L Wencel

doi:10.1007/s12035-016-0317-1

J Motyl, M Cieślik + Show 3 more

Open Access

https://doi.org/10.1007/s12035-016-0317-1

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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.

Highlights

Alpha-synuclein (ASN) is a 140-amino acid soluble protein that is abundantly expressed in the nervous system, where it constitutes 1% of total cytosolic proteins [1,2,3]
The study was focused on the role of Extracellular alphasynuclein (eASN) in regulation of gene expression of sirtuins, DNA-bound poly(ADP-ribose) polymerases (PARPs) and other stress response proteins engaged in regulation of cell survival/death
The upregulation of SIRT1 leads to suppression of Aβ production by activation of alpha-secretase [51, 53]. eASN may translocate from extracellular compartment inside the cell and it can influence gene expression directly or by interaction with different transcription factors, this process is not fully understood [66]

Summary

Introduction

Alpha-synuclein (ASN) is a 140-amino acid soluble protein that is abundantly expressed in the nervous system, where it constitutes 1% of total cytosolic proteins [1,2,3]. Recent data have indicated that alterations in ASN expression and conformation could play an important role in familial (A30P, A53T mutations) and in sporadic forms of Parkinson’s disease (PD) as well as in the pathology of about 60% of Alzheimer’s disease’s (AD) cases [10,11,12,13]. Misfolding of this protein leads to aggregation/ fibrilisation of ASN, which in β-sheet structure is toxic to cells [14,15,16]. The mechanism of ASN secretion is not well understood, oxidative stress seems to have a promoting role in this process [12, 22, 29]

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