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Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson's disease: ex vivo and in vitro studies.
J Neuroinflammation. 2018 Jun 04; 15(1):172.JN

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 of α-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 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.

RESULTS

Co-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.

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 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.

Links

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Authors+Show Affiliations

Horvath I
Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden.
Iashchishyn IA
Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden. Department of General Chemistry, Sumy State University, Sumy, 40007, Ukraine.
Moskalenko RA
Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden. Department of Pathology, Sumy State University, Sumy, 40007, Ukraine.
Wang C
Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden.
Wärmländer SKTS
Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden.
Wallin C
Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden.
Gräslund A
Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden.
Kovacs GG
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Morozova-Roche LA
Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden. ludmilla.morozova-roche@umu.se.

MeSH

AgedAged, 80 and overAmyloidAutopsyBrainCalgranulin BCell Line, TumorCircular DichroismFemaleHumansLewy BodiesMagnetic Resonance SpectroscopyMaleMicroscopy, Electron, ScanningNeuroblastomaParkinson DiseaseProtein AggregatesStatistics, NonparametricSurface Plasmon Resonancealpha-Synuclein

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29866153

Citation

Horvath, Istvan, et al. "Co-aggregation of Pro-inflammatory S100A9 With Α-synuclein in Parkinson's Disease: Ex Vivo and in Vitro Studies." Journal of Neuroinflammation, vol. 15, no. 1, 2018, p. 172.
Horvath I, Iashchishyn IA, Moskalenko RA, et al. Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson's disease: ex vivo and in vitro studies. J Neuroinflammation. 2018;15(1):172.
Horvath, I., Iashchishyn, I. A., Moskalenko, R. A., Wang, C., Wärmländer, S. K. T. S., Wallin, C., Gräslund, A., Kovacs, G. G., & Morozova-Roche, L. A. (2018). Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson's disease: ex vivo and in vitro studies. Journal of Neuroinflammation, 15(1), 172. https://doi.org/10.1186/s12974-018-1210-9
Horvath I, et al. Co-aggregation of Pro-inflammatory S100A9 With Α-synuclein in Parkinson's Disease: Ex Vivo and in Vitro Studies. J Neuroinflammation. 2018 Jun 4;15(1):172. PubMed PMID: 29866153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson's disease: ex vivo and in vitro studies. AU - Horvath,Istvan, AU - Iashchishyn,Igor A, AU - Moskalenko,Roman A, AU - Wang,Chao, AU - Wärmländer,Sebastian K T S, AU - Wallin,Cecilia, AU - Gräslund,Astrid, AU - Kovacs,Gabor G, AU - Morozova-Roche,Ludmilla A, Y1 - 2018/06/04/ PY - 2018/02/20/received PY - 2018/05/20/accepted PY - 2018/6/6/entrez PY - 2018/6/6/pubmed PY - 2019/4/11/medline KW - Amyloid KW - Cytotoxicity KW - Neuroinflammation KW - Parkinson’s disease KW - S100A9 KW - α-Synuclein SP - 172 EP - 172 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 15 IS - 1 N2 - 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 α-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 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. RESULTS: Co-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. 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 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/29866153/Co_aggregation_of_pro_inflammatory_S100A9_with_α_synuclein_in_Parkinson's_disease:_ex_vivo_and_in_vitro_studies_ DB - PRIME DP - Unbound Medicine ER -