Inflammation promotes synucleinopathy propagation

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of alpha-synuclein (V40G) was much less capable of fibril formation than wild-type alpha-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of alpha-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.

Automated summary

This article proposes that inflammation plays a fundamental role in the spread of proteinopathy. Experiment results show that a variant of alpha-synuclein interferes with fibrillation when mixed with the wild-type protein, but induces more effective aggregate spreading when injected into mouse brains. This spreading process is accompanied by sustained microgliosis and inflammatory responses, which can be suppressed by an anti-inflammatory agent. Cell experiments also demonstrate that exposure to inflammatory cytokines increases the cell-to-cell propagation of alpha-synuclein.