Tae-Kyung Kim # 1 2, Eun-Jin Bae # 1 3, Byung Chul Jung # 1 4, Minsun Choi 1, Soo Jean Shin 1, Sung Jun Park 1, Jeong Tae Kim 1, Min Kyo Jung 5, Ayse Ulusoy 6, Mi-Young Song 7 8, Jun Sung Lee 1 9, He-Jin Lee 10 11, Donato A Di Monte 6, Seung-Jae Lee 12 13 14 15
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
2Department of Exercise Physiology and Sport Science Institute, Korea National Sport University, Seoul, 05541, Korea.
3Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
4Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, 94720, USA.
5Neural Circuits Research Group, Korea Brain Research Institute, Daegu, 41068, Korea.
6German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
7Department of Biomedical Science and Technology, Konkuk University, Seoul, 143-701, Korea.
8IPS Intellectual Property Law Firm, Seoul, Korea.
9Neuramedy Co. Ltd., Seoul, South Korea.
10Department of Anatomy, Konkuk University, Seoul, 05029, Korea.
11IBST, Konkuk University, Seoul, 05029, Korea.
12Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
13Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
14SNU Dementia Research Center, Seoul National University College of Medicine, Seoul, South Korea.
15Neuramedy Co. Ltd., Seoul, South Korea.
Corresponding author : Correspondence to Seung-Jae Lee.
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.