Toll-like Receptor 4 Is Upregulated in Parkinson’s Disease Patients and Co-Localizes with pSer129αSyn: A Possible Link with the Pathology

Abstract

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.

Keywords

• Parkinson’s disease
• neuroinflammation
• alpha-synuclein
• substantia nigra pars compacta
• middle temporal gyrus