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Title Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
Authors Horvath, I.
Yashchishyn, Ihor Oleksandrovych  
Moskalenko, Roman Andriiovych  
Wang, C.
Wärmländer, S.K.T.S.
Wallin, C.
Gräslund, A.
Kovac, G.G.
Morozova-Roche, L.A.
ORCID http://orcid.org/0000-0002-1691-9025
http://orcid.org/0000-0002-2342-0337
Keywords S100A9
α-синуклеїн
α-синуклеин
α-Synuclein
хвороба Паркінсона
болезнь Паркинсона
Parkinson’s disease
амілоїд
амилоид
Amyloid
запалення нервової тканини
воспаление нервной ткани
Neuroinflammation
Type Article
Date of Issue 2018
URI http://essuir.sumdu.edu.ua/handle/123456789/68102
Publisher BMC
License
Citation Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies / I. Horvath, I.A. Iashchishyn, R.A. Moskalenko [et al.] // Journal of Neuroinflammation. - 2018. - 15:172. - https://doi.org/10.1186/s12974-018-1210-9.
Abstract Background:Chronic neuroinflammation is a hallmark of Parkinson’s disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer’s disease. This is the first report on the co-aggregation ofα-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. Methods:Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze theex vivo PD brain tissues for S100A9 andα-syn location and aggregation. In vitro studies revealing S100A9 andα-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Results:Co-localized and co-aggregated S100A9 andα-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4–6). Lewy bodies were characterized by ca. 10–23μm outer diameter, with S100A9 andα-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 andα-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissociation constant of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those ofα-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. Conclusions:We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβco-aggregation in Alzheimer’s disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues
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