Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease

Parkinson's disease (PD) is an age-related movement disorder characterized by a progressive degeneration of dopaminergic neurons in the midbrain. Although the presence of amyloid deposits of alpha-synuclein (alpha-syn) is the main pathological feature, PD brains also present a severe permanent inflammation, which largely contributes to neuropathology. Although alpha-syn has recently been implicated in this process, the molecular mechanisms underlying neuroinflammation remain unknown. In the present study, we investigated the ability of different alpha-syn aggregates to trigger inflammatory responses. We showed that alpha-syn induced inflammation through activation of Toll-like receptor 2 (TLR2) and the nucleotide oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome only when folded as amyloid fibrils. Oligomeric species, thought to be the primary species responsible for the disease, were surprisingly unable to trigger the same cascades. As neuroinflammation is a key player in PD pathology, these results put fibrils back to the fore and rekindles discussions about the primary toxic species contributing to the disease. Our data also suggest that the inflammatory properties of alpha-syn fibrils are linked to their intrinsic structure, most probably to their cross-beta structure. Since fibrils of other amyloids induce similar immunological responses, we propose that the canonical fibril-specific cross-beta structure represents a new generic motif recognized by the innate immune system.