Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies

Abstract

BackgroundChronic 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 α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain.MethodsSingle and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods.ResultsCo-localized and co-aggregated S100A9 and α-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 μm outer diameter, with S100A9 and α-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 α-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 of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers.ConclusionsWe 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 Aβ 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1210-9) contains supplementary material, which is available to authorized users.

Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies

“…This is supported by the SPR data showing that aSyn monomers and PFFs interact with HSP10 with high affinity. In comparison, the dissociation constants obtained in the SPR experiment were identical to those described for aSyn and S100A9 interaction (Horvath et al, 2018). In addition, we found a significant fraction of HSP10 in the cytoplasm, alongside decreased levels of mitochondrial HSP10.…”

“…Interestingly, the levels of HSP10 limit the formation of the symmetric complexes, and the asymmetric complex has reduced folding capacity (Nisemblat et al, 2015). Because the HSP10/HSP60 complex is one of the most important players in mitochondrial quality control (Horwich et al, 2007;Campos et al, 2016), reduced function of the complex results in embryonic lethality (Christensen et al, 2010), and a heterozygous mutation in the HSPE1 gene associates with severe, early-onset neurological disorder in humans (Bie et al, 2016). Although the mutant protein is functional, its resistance to proteases is substantially reduced, resulting in an almost 2-fold reduction in the HSP10/HSP60 ratio.…”

Apoptosis and its Role in Parkinson’s Disease

“…It is prone to fibrillar aggregation forming a major component of the Lewy bodies that are the pathological hallmark of Parkinson' s disease (65). α-synuclein aggregates and inclusions are formed in Parkinson' s disease brains, and rodents and cells treated with mitochondrial toxins (66)(67)(68). Accumulation of wild-type α-synuclein in dopaminergic neurons leads to decreased activity of mitochondrial complex I and increased reactive oxygen species generation-an effect which is more pronounced by the expression of the aggregation-prone mutant A53T α-synuclein (69).…”

S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer’s Disease

“…A widespread expression of S100A9 was reported in many ailments associated with inflammatory processes, such as AD 10 , 32 , Parkinson’s disease 33 , malaria 34 , cerebral ischemia 35 , TBI 36 , obesity 37 and cardiovascular disease 38 , implying that S100A9 may be a universal biomarker of inflammation. The abundance of S100A9 mRNA was also identified as a strong feature of aging in various mammalian tissues, including the central nervous system, and a novel mechanism of the age-associated inflammation sustained by S100A9 was suggested 39 .…”