title: Alpha-synuclein alters differently gene expression of Sirts, PARPs and other stress response proteins: implications for neurodegenerative disorders.
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.
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Motyl
authors.affiliation: Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, 02-106, Warsaw, Poland.
authors.forename: P L
authors.initials: PL
authors.lastname: Wencel
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Cieślik
authors.affiliation: Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, 02-106, Warsaw, Poland. rstrosznajder@imdik.pan.pl.
authors.forename: R P
authors.initials: RP
authors.lastname: Strosznajder
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland.
authors.forename: J B
authors.initials: JB
authors.lastname: Strosznajder
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000975:Antioxidants; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D011065:Poly(ADP-ribose) Polymerases; D037761:Sirtuins
keywords: AD; Alpha-synuclein; Amyloid; Neurodegeneration; PARPs; Sirtuins