Journal
NEUROBIOLOGY OF DISEASE
Volume 73, Issue -, Pages 244-253Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.10.011
Keywords
alpha-Synudein; Fibril; Aggregate formation; Cathepsin B; Lysosome
Categories
Funding
- NICHD
- National Institutes of Health,
- Japan Society for Promotion of Science [YW: 24591272, MT: 25290014]
- Japan Science and Technology Agency [MT: AS242Z01075Q]
- Grants-in-Aid for Scientific Research [24591272, 25640024] Funding Source: KAKEN
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The formation of intracellular aggregates containing alpha-synuclein (alpha-Syn) is one of the key steps in the progression of Parkinson's disease and dementia with Lewy bodies. Recently, it was reported that pathological a-Syn fibrils can undergo cell-to-cell transmission and form Lewy body-like aggregates. However, little is known about how they form a-Syn aggregates from fibril seeds. Here, we developed an assay to study the process of aggregate formation using fluorescent protein-tagged alpha-Syn-expressing cells and examined the aggregate forming activity of exogenous a-Syn fibrils. alpha-Syn fibril-induced formation of intracellular aggregates was suppressed by a cathepsin B specific inhibitor, but not by a cathepsin D inhibitor. a-Syn fibrils pretreated with cathepsin B in vitro enhanced seeding activity in cells. Knockdown of cathepsin B also reduced fibril-induced aggregate formation. Moreover, using LAMP-1 immunocytochemistry and live-cell imaging, we observed that these aggregates initially occurred in the lysosome. They then rapidly grew larger and moved outside the boundary of the lysosome within one day. These results suggest that the lysosomal protease cathepsin B is involved in triggering intracellular aggregate formation by a-Syn fibrils. (C) 2015 Elsevier Inc.
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