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Inflammation drives synucleinopathy propagation

Authors :
Minsun Choi
Ayse Ulusoy
Byung Chul Jung
Soo-Jean Shin
Jeong Tae Kim
Tae-Kyung Kim
Seung-Jae Lee
He-Jin Lee
Jun Sung Lee
Donato A. Di Monte
Min-kyo Jung
Mi-Young Song
Eun-Jin Bae
Publication Year :
2021
Publisher :
Research Square Platform LLC, 2021.

Abstract

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. Understanding of the mechanism of the proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. Yet when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. The 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 α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........ad697b2f35a495a016c5be57719696df