Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril

Abstract

A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate “strains” with distinct structures. Among the amyloidogenic proteins, α-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive. Here we show that in the presence of bacterial endotoxin, lipopolysaccharide (LPS), α-synuclein generated a self-renewable, structurally distinct fibril strain that consistently induced specific patterns of synucleinopathies in mice. These results suggest that amyloid fibrils with self-renewable structures cause distinct types of proteinopathies despite the identical primary structure and that exposure to exogenous pathogens may contribute to the diversity of synucleinopathies.

Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal α-synucleinopathy

“…Second, in contrast to MPLA, LPS had a strong effect on the re-distribution from non-toxic soluble monomeric to toxic insoluble oligomeric α-syn species in the brains of PLP-α-syn mice. This finding is supported by recent data reporting that LPS may directly (without the mediatory effect of neuroinflammatory responses) trigger the generation of distinct α-syn fibrils in vitro [50]. In summary, although LPS, like MPLA, is found to induce equally strong phagocytic activity in microglial cells and similar neuroinflammatory response is elicited after chronic systemic treatment, its beneficial effects are limited due to the deleterious effects on α-syn aggregation and the general pro-inflammatory response elicited in the plasma.…”

α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties

“…This suggests that residues 4 to 95 contain the inaccessible backbone amide hydrogens, while C-terminus (residues 96 to 140) is mostly disordered. Interestingly, the segments spanning residues 18 to 95 showed a bimodal mass distribution for all the fibrils (Figure 2c, Figure S3), indicating the existence of two 6 different fibrillar conformations as observed previously for α-Syn oligomers and fibrils 21,31,32 .…”

“…Further to gain residue/segment-specific information for the possible differences in the fibril core of HMF and PMF, we performed HDX-MS analysis [29][30][31] . For all the fibril polymorphs, residues 4 to 95 remained highly protected (unlabeled similar to 0 % deuterated α-Syn monomer peaks) in contrast to C-terminal residues 96 to 140 (labeled similar to the 95 % deuterated monomer peaks) (Figure 2c, Figure S2 and S3).…”

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

“…However, the results of our motor tests are not readily explained by sex differences in TH or DAT expression in the nigrostriatal pathway and may therefore be mediated by extranigral neural circuitry, such as the sensorimotor cortex or cerebellum, or by sex‐dependent differences in electrophysiological activity that are not captured by simple histological assays. Kim and colleagues reported a lack of gender differences following infusions of preformed fibrils in the striatum of wild‐type mice, supporting the view that the induction site and the route of spread are critical . However, Cantuti‐Castelvetri and colleagues observed that nigral dopamine neurons in male subjects display higher baseline expression of α‐synuclein protein , suggesting that males may have more endogenous α‐synuclein molecules available as a substrate for seeding and aggregation.…”