|Title||Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies|
Yashchishyn, Ihor Oleksandrovych
Moskalenko, Roman Andriiovych
запалення нервової тканини
воспаление нервной ткани
|Date of Issue||2018|
|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.|
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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