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

Abstract

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 α-synuclein (α-syn) is the main pathological feature, PD brains also present a severe permanent inflammation, which largely contributes to neuropathology. Although α-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 α-syn aggregates to trigger inflammatory responses. We showed that α-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 α-syn fibrils are linked to their intrinsic structure, most probably to their cross-β structure. Since fibrils of other amyloids induce similar immunological responses, we propose that the canonical fibril-specific cross-β structure represents a new generic motif recognized by the innate immune system.

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

“…In brain, the innate immune response is perceived to be mediated by glial cells, and it has been demonstrated that α-synuclein can activate microglia [1, 3, 21, 39, 47]. Both oligomeric [19] and fibrilar [15] forms of α-synuclein have been shown to activate microglial TLR2 in tissue culture experiments. In addition, monomeric α-synuclein may potentiate inflammatory cytokine production by microglial cells stimulated with TLR agonists, in particular the prototypical TLR2 agonist PAM3CSK4 [35].…”

“…As well as forming insoluble Lewy body aggregates in PD brain, α-synuclein also forms monomers, oligomers, fibrils and other conformations [44]. The exact contribution of different α-synuclein conformations to TLR activation is currently unclear; however, it has been demonstrated that α-synuclein can at least activate the TLR2 receptor on microglia and promote inflammatory cytokine production [9, 15, 19]. Moreover, α-synuclein can increase the expression of TLRs [4], suggesting that brain regions that accumulate α-synuclein in PD may have increased TLR2 protein.…”

α-Synuclein Amyloid Fibrils with Two Entwined, Asymmetrically Associated Protofibrils

“…There have been some indications that different strains give rise to different synucleinopathies (42) and that ␣S fibrils stimulate inflammation (43). These considerations motivate additional efforts to develop better structural models of ␣S fibrils and to define their relation to clinical isolates as a basis for understanding the mechanism of disease development.…”

The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome

“…Several inflammasome complexes have been described to date, however the NLRP3 inflammasome is of special interest because of its ability to recognize a wide range of noxious substances. Importantly, dysregulation of the NLRP3 inflammasome is being recognized as the common feature of a wide spectrum of chronic inflammatory and metabolic diseases, such as, gout, rheumatoid arthritis, osteoarthritis, Alzheimer's disease, Parkinson's disease, type-2 diabetes, and obesity [6][7][8][9][10][11][12][13][14].…”