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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-016-0317-1) contains supplementary material, which is available to authorized users.

Emerging Role of Sirtuin 2 in Parkinson’s Disease

“…SIRT1 deacetylase activity mediates clearance of α-syn through light chain 3 (LC3) mediated autophagy to protect against PD pathology (Guo et al, 2016). Moreover, extracellular α-syn accumulation leads to mitochondrial dysfunction and a reduction of SIRT1 expression (Motyl et al, 2018). One the other hand, the upregulation, and activation of SIRT1 could activate peroxisome proliferator-activated receptor γ co-activator 1 (PGC-1α) to confer DA neuron protection against oxidative stress (Mäkelä et al, 2016).…”

Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology

“…It has been demonstrated that LAG3 proteolytic cleavage can be carried out by ADAM17 and ADAM10, two membrane metalloproteases, resulting in the generation of sLAG3 [74]. Interestingly, extracellular α-synuclein may downregulate the expression of ADAM10, whose role has been already established in Alzheimer's disease pathogenesis [75]. Thus, a low activity of ADAM17 and ADAM10 may represent the reason of decreased sLAG3 levels in the CSF of PD patients [40].…”

Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models

“…Instead of invoking the downregulation of pro-survival gene expression [62][63][64], we provide an alternative mechanistic explanation to how the transcriptional derepression of a pro-apoptotic gene can participate in the pathogenesis of neurodegenerative disorders. Instead of invoking the downregulation of pro-survival gene expression [62][63][64], we provide an alternative mechanistic explanation to how the transcriptional derepression of a pro-apoptotic gene can participate in the pathogenesis of neurodegenerative disorders.…”