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Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of General Chemistry, Sumy State University, Sumy 40007, Ukraine.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. 3 Department of Pathology, Sumy State University, Sumy 40007, Ukraine.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0001-7505-8045
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2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 172Article in journal (Refereed) Published
Abstract [en]

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 of alpha-synuclein (alpha-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 the ex vivo PD brain tissues for S100A9 and alpha-syn location and aggregation. In vitro studies revealing S100A9 and alpha-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 and alpha-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. 10-23 mu m outer diameter, with S100A9 and alpha-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 and alpha-syn were shown to interact with each other via the alpha-syn C-terminus with an apparent dissociation constant of ca. 5 mu M. 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 of alpha-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 alpha-syn and S100A9 and leading to PD, similar to the effect of S100A9 and A beta co-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.

Place, publisher, year, edition, pages
BioMed Central, 2018. Vol. 15, article id 172
Keywords [en]
S100A9, alpha-Synuclein, Parkinson's disease, Neuroinflammation, Amyloid, Cytotoxicity
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-150174DOI: 10.1186/s12974-018-1210-9ISI: 000434209800001PubMedID: 29866153OAI: oai:DiVA.org:umu-150174DiVA, id: diva2:1233507
Funder
Västerbotten County Council, ALFVLL-369861Swedish Research Council, 2014-3241The Swedish Brain FoundationAvailable from: 2018-07-18 Created: 2018-07-18 Last updated: 2018-07-19Bibliographically approved

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Horvath, IstvanIashchishyn, IgorMoskalenko, Roman A.Wang, ChaoMorozova-Roche, Ludmilla

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