Effects Of Innate Immune Receptor Stimulation On Extracellular Alpha-Synuclein Uptake And Degradation By Brain Resident Cells

Synucleinopathies are age-related neurological disorders characterized by the progressive deposition of alpha-synuclein (alpha-syn) aggregates and include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell alpha-syn transmission is thought to play a key role in the spread of alpha-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of alpha-syn aggregates varies from study to study, and how different alpha-syn aggregate species interact with innate immune receptors has yet to be addressed. Therefore, we investigated whether innate immune receptors can facilitate the uptake of different species of alpha-syn aggregates. Here, we examined whether stimulation of TLRs could modulate the cellular uptake and degradation of alpha-syn fibrils despite a lack of direct interaction. We observed that stimulation of TLR2 in vitro accelerated alpha-syn fibril uptake in neurons and glia while delaying the degradation of alpha-syn in neurons and astrocytes. Internalized alpha-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular alpha-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a synucleinopathy mouse model increased the density of Lewy-body-like inclusions and induced morphological changes in microglia. Together, these results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic alpha-syn transmission, but activation of microglial TLR2 enhances microglial extracellular alpha-syn clearance.Neurological disease: New target to stop harmful protein build-up New treatments for neurological disorders could target immune receptors associated with the build-up of protein aggregates in neurons. Synucleinopathies are characterized by abnormal deposition of alpha-synuclein, but the mechanism how alpha-synuclein spreads between cells is still elusive. Changyoun Kim and Eliezer Masliah at the National Institutes of Health in Bethesda, USA, and co-workers investigated indirect role of TLR2 in alpha-synuclein spreading. TLR2 has been known to interact with beta-sheet-enriched oligomeric forms of alpha-synuclein, but not with fibrilar forms of alpha-synuclein (fibril). Herein, the authors found that TLR2 stimulation accelerated the uptake of fibrils in both neurons and glial cells, delayed degradation of internalized fibrils and worsen alpha-synuclein pathology in mouse brains. The study provides indirect modulation of alpha-synuclein spearding via innate immune receptor which might be a potential therapy for synucleinopathies.