Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson's Disease

We investigated alpha-synuclein's (alpha Syn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic alpha Syn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson's disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant alpha Syn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson's disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric alpha Syn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients >= 80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic alpha Syn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic alpha Syn in a particular region at a given neuropathological stage.

Automated summary

The study found that fixed tissue from Parkinson's disease and incidental Lewy body disease can promote the aggregation of monomeric alpha Syn into fibrillar assemblies, with significant variations in fibrillar assembly characteristics between regions and shorter lag phases in patients aged 80 and above.