TY - JOUR
T1 - Toll-like Receptor 4 Is Upregulated in Parkinson’s Disease Patients and Co-Localizes with pSer129αSyn
T2 - A Possible Link with the Pathology
AU - Conte, Carmela
AU - Ingrassia, Angela
AU - Breve, John
AU - Bol, John J.
AU - Timmermans-Huisman, Evelien
AU - van Dam, Anne-Marie
AU - Beccari, Tommaso
AU - van de Berg, Wilma D. J.
N1 - Funding Information: W.D.J.v.d.B. was financially supported by grants from Amsterdam Neuroscience, Dutch Research Council (ZonMW 70-73305-98-106; 70-73305-98-102; 40-46000-98-101), Stichting Parkinson Fonds (Insula 2014–2019), Alzheimer Association (AARF-18-566459), MJ Fox Foundation (17253), Parkinson Association (2020-G01) and Health Holland. W.D.J.v.d.B. performed contract research for Roche Tissue Diagnostics, Crossbeta Sciences, Discoveric Bio and received research consumables from Hoffmann-La Roche and Prothena. C.C. was financially supported by Fondo Ricerca di Base di Ateneo, University of Perugia, Perugia, Italy, grant number 6RICBASE21. Publisher Copyright: © 2023 by the authors.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in pyramidal neurons in the GTM of PD donors. Furthermore, we observed a co-localization of TLR4 and Iba-1 in glial cells of both SN and GTM. Our findings provide evidence for the increased expression of TLR4 in the PD brain and suggest that the interaction between TLR4 and pSer129-αSyn could play a role in mediating the neuroinflammatory response in PD.
AB - Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in pyramidal neurons in the GTM of PD donors. Furthermore, we observed a co-localization of TLR4 and Iba-1 in glial cells of both SN and GTM. Our findings provide evidence for the increased expression of TLR4 in the PD brain and suggest that the interaction between TLR4 and pSer129-αSyn could play a role in mediating the neuroinflammatory response in PD.
KW - Parkinson’s disease
KW - alpha-synuclein
KW - middle temporal gyrus
KW - neuroinflammation
KW - substantia nigra pars compacta
UR - http://www.scopus.com/inward/record.url?scp=85160663502&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells12101368
DO - https://doi.org/10.3390/cells12101368
M3 - Article
C2 - 37408202
SN - 2073-4409
VL - 12
JO - Cells
JF - Cells
IS - 10
M1 - 1368
ER -