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KMID : 0620920220540122148
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Experimental & Molecular Medicine
2022 Volume.54 No. 12 p.2148 ~ p.2161
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Inflammation promotes synucleinopathy propagation
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Kim Tae-Kyung
Bae Eun-Jin
Jung Byung-Chul
Choi Min-Sun
Shin Soo-Jean
Park Sung-Jun
Kim Jeong-Tae
Jung Min-Kyo
Ulusoy Ayse
Song Mi-Young
Lee Jun-Sung
Lee He-Jin
Di Monte Donato A.
Lee Seung-Jae
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Abstract
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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 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. 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 α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.
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