Abstract
Despite the wealth of genomic and transcriptomic data in Parkinson’s disease (PD), the initial molecular events are unknown. Using LD score regression analysis, we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiological concentrations of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF-α production. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of alpha-synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD.
Highlights
Parkinson’s disease (PD) is a common progressive neurodegenerative disease with motor-related symptoms including tremor, bradykinesia and rigidity and characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies containing deposits of the protein10 Present AddressWeizmann Institute of Science, Perlman Chemical Sciences Building, Room 601, 76100 Rehovot, Israel1 3 Vol.:(0123456789)Acta Neuropathologica (2019) 137:103–120 alpha-synuclein (α-syn)
We used transcriptomic data from humans as a starting point to determine the relevance of TLR2 and TLR4 signalling in the initiation of PD
Our analysis of human brain transcriptomic data shows that of all brain regions analyzed, the substantia nigra has the highest levels of TLR4 expression
Summary
TLR4 promoted α-syn clearance in a synucleinopathy protein aggregation mouse model [45]. These contrasting results highlight the importance of establishing the initial events that cause PD in humans and the role played by TLRs. The role of TLRs in the development of PD is currently unclear because the in vitro studies to date have used 1000-fold higher protein aggregate concentrations than those found in the human disease (estimated at 1–10 pM oligomers in CSF [19, 47]), containing large uncharacterized aggregates over short time courses.
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