Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson's Disease Etiopathology.

Mol Neurobiol. 2018 Apr 21. doi: 10.1007/s12035-018-1082-0. [Epub ahead of print]

Wilkaniec A1, Lenkiewicz AM1, Czapski GA1, Jęśko HM1, Hilgier W2, Brodzik R3, Gąssowska-Dobrowolska M1, Culmsee C4, Adamczyk A5.

Author information:

1 Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Street, 02-106, Warsaw, Poland.

2 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Street, 02-106, Warsaw, Poland.

3 BLIRT S.A., Trzy Lipy 3/1.38, 80-172, Gdańsk, Poland.

4 Institute of Pharmacology and Clinical Pharmacy, University of Marburg, 35043, Marburg, Germany.

5 Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Street, 02-106, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

 

ABSTRACT:

α-Synuclein (ASN) and parkin, a multifunctional E3 ubiquitin ligase, are two proteins that are associated with the pathophysiology of Parkinson's disease (PD). Excessive release of ASN, its oligomerization, aggregation, and deposition in the cytoplasm contribute to neuronal injury and cell death through oxidative-nitrosative stress induction, mitochondrial impairment, and synaptic dysfunction. In contrast, overexpression of parkin provides protection against cellular stresses and prevents dopaminergic neural cell loss in several animal models of PD. However, the influence of ASN on the function of parkin is largely unknown. Therefore, the aim of this study was to investigate the effect of extracellular ASN oligomers on parkin expression, S-nitrosylation, as well as its activity. For these investigations, we used rat pheochromocytoma (PC12) cell line treated with exogenous oligomeric ASN as well as PC12 cells with parkin overexpression and parkin knock-down. The experiments were performed using spectrophotometric, spectrofluorometric, and immunochemical methods. We found that exogenous ASN oligomers induce oxidative/nitrosative stress leading to parkin S-nitrosylation. Moreover, this posttranslational modification induced the elevation of parkin autoubiquitination and degradation of the protein. The decreased parkin levels resulted in significant cell death, whereas parkin overexpression protected against toxicity induced by extracellular ASN oligomers. We conclude that lowering parkin levels by extracellular ASN may significantly contribute to the propagation of neurodegeneration in PD pathology through accumulation of defective proteins as a consequence of parkin degradation.

KEYWORDS:

Alpha-synuclein; Parkin; Parkinson’s disease; S-nitrosylation

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