Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

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.

Formal model of Parkinson’s disease neurons unveils possible causality links in the pathophysiology of the disease

“…In this scenario the activation of α -synuclein translation upon iron accumulation reaching a critical value followed by protein aggregation into oligomers and fibrils that can form Lewy Bodies was investigated. The average concentration of oligomers found in PD brains was reported to be at around 10 pM (Hansson et al, 2014;Horrocks et al, 2016;Hughes et al, 2019). This concentration yields approximately 100 to 1000 oligomers corresponding to 1 to 10 Lewy Body/fibrils in our model.…”

Association Between Toll‐Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease

“…TLR4, a pattern recognition receptor, has also been associated with misfolded protein clearance. For instance, the uptake of α‐synuclein by microglia has been shown to depend at least in part on TLR4 in models of α‐synucleinopathies . This receptor is also responsible for the α‐synuclein‐induced proinflammatory response in astrocytes and triggers the amyloid‐β‐induced activation of microglia in AD models .…”

“…For instance, the uptake of α-synuclein by microglia has been shown to depend at least in part on TLR4 in models of α-synucleinopathies. 45,46 This receptor is also responsible for the α-synuclein-induced proinflammatory response in astrocytes 47 and triggers the amyloid-β-induced activation of microglia in AD models. 48 As such, it is not unexpected that TLR4 is also involved in the inflammatory response in HD.…”

Potent inhibitors of toxic alpha-synuclein oligomers identified via cellular time-resolved FRET biosensor

“…Lewy bodies are a shared, fibrillar, pathological hallmark of many alpha-synucleinopathies. These fibrillar inclusion have been posited to be contain neurotoxic species with a direct link to the prion-like, cell-to-cell spread of pathology throughout the central nervous system 31,[42][43][44][45][46][47] . Indeed, numerous rodent models have been developed using intramuscular or intra-striatal injection of sonicated pre-formed fibrils (PFF) and produce robust and temporally staged PD-like pathology 44,[48][49][50][51][52][53] .…”

“…Indeed, numerous rodent models have been developed using intramuscular or intra-striatal injection of sonicated pre-formed fibrils (PFF) and produce robust and temporally staged PD-like pathology 44,[48][49][50][51][52][53] . Although fibrils are present in the end-stage pathology of alpha-synucleinopathy, biochemical analysis of early stage transgenic animals suggest that the initial neuronal insult is associated with soluble aSyn oligomers, providing an additional pathological target for potential therapeutic intervention 11,15,19,42,[54][55][56][57][58] .…”