Crosstalk Between Alpha-Synuclein and Other Human and Non-Human Amyloidogenic Proteins: Consequences for Amyloid Formation in Parkinson's Disease

Abstract

It was recently shown (Sampson et al., Elife9, 2020) that an amyloidogenic protein, CsgA, present in E. coli biofilms in the gut can trigger Parkinson's disease in mice. This study emphasizes the possible role of the gut microbiome in modulation (and even initiation) of human neurodegenerative disorders, such as Parkinson's disease. As the CsgA protein was found to accelerate alpha-synuclein (the key amyloidogenic protein in Parkinson's disease) amyloid formation in vitro, this result suggests that also other amyloidogenic proteins from gut bacteria, and even from the diet (such as stable allergenic proteins), may be able to affect human protein conformations and thereby modulate amyloid-related diseases. In this review, we summarize what has been reported in terms of in vitro cross-reactivity studies between alpha-synuclein and other amyloidogenic human and non-human proteins. It becomes clear from the limited data that exist that there is a fine line between acceleration and inhibition, but that cross-reactivity is widespread, and it is more common for other proteins (among the studied cases) to accelerate alpha-synuclein amyloid formation than to block it. It is of high importance to expand investigations of cross-reactivity between amyloidogenic proteins to both reveal underlying mechanisms and links between human diseases, as well as to develop new treatments that may be based on an altered gut microbiome.

Keywords: Parkinson’s disease; alpha-synuclein; amyloid formation; cross-reactivity; food allergens; functional amyloids; microbiome; neurodegeneration.

Fig. 1

A) Scheme of aS’s polypeptide with N-terminal (blue), NAC (yellow) and C-terminal (red) parts indicated as well as known disease-causing mutations (stars). B) Typical aggregation curve of aS as probed by ThT fluorescence (lag, growth and plateau phases indicated). C) AFM image of aS amyloid fibers. D) High-resolution structures (2N0A, 6A6B, 6FLT, 6CU7, and 6CU8; Table 1) of aS amyloid fiber cores.

Fig. 2

Illustration of the cross-reactivity results reported in Table 2, indicating the amyloidogenic proteins (as monomers or amyloids) that accelerate aS amyloid formation (bottom box) and the ones that reduce/block aS aggregation (top box).