Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils
The formation of intracellular aggregates containing α-synuclein (α-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 α-Syn fibrils can undergo cell-to-cell transmission and form Lewy body-like aggre...
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doaj-13204aabcb5a4e2ca880d308ba3bb0082021-03-22T12:42:03ZengElsevierNeurobiology of Disease1095-953X2015-01-0173244253Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrilsAtsushi Tsujimura0Katsutoshi Taguchi1Yoshihisa Watanabe2Harutsugu Tatebe3Takahiko Tokuda4Toshiki Mizuno5Masaki Tanaka6Department of Basic Geriatrics, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, JapanDepartment of Basic Geriatrics, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, JapanDepartment of Basic Geriatrics, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, JapanDepartment of Neurology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, JapanDepartment of Neurology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, JapanDepartment of Neurology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, JapanDepartment of Basic Geriatrics, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan; Corresponding author. Fax: +81 75 251 5797.The formation of intracellular aggregates containing α-synuclein (α-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 α-Syn fibrils can undergo cell-to-cell transmission and form Lewy body-like aggregates. However, little is known about how they form α-Syn aggregates from fibril seeds. Here, we developed an assay to study the process of aggregate formation using fluorescent protein-tagged α-Syn-expressing cells and examined the aggregate forming activity of exogenous α-Syn fibrils. α-Syn fibril-induced formation of intracellular aggregates was suppressed by a cathepsin B specific inhibitor, but not by a cathepsin D inhibitor. α-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 α-Syn fibrils.http://www.sciencedirect.com/science/article/pii/S0969996114003040α-SynucleinFibrilAggregate formationCathepsin BLysosome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Atsushi Tsujimura Katsutoshi Taguchi Yoshihisa Watanabe Harutsugu Tatebe Takahiko Tokuda Toshiki Mizuno Masaki Tanaka |
spellingShingle |
Atsushi Tsujimura Katsutoshi Taguchi Yoshihisa Watanabe Harutsugu Tatebe Takahiko Tokuda Toshiki Mizuno Masaki Tanaka Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils Neurobiology of Disease α-Synuclein Fibril Aggregate formation Cathepsin B Lysosome |
author_facet |
Atsushi Tsujimura Katsutoshi Taguchi Yoshihisa Watanabe Harutsugu Tatebe Takahiko Tokuda Toshiki Mizuno Masaki Tanaka |
author_sort |
Atsushi Tsujimura |
title |
Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils |
title_short |
Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils |
title_full |
Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils |
title_fullStr |
Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils |
title_full_unstemmed |
Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils |
title_sort |
lysosomal enzyme cathepsin b enhances the aggregate forming activity of exogenous α-synuclein fibrils |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2015-01-01 |
description |
The formation of intracellular aggregates containing α-synuclein (α-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 α-Syn fibrils can undergo cell-to-cell transmission and form Lewy body-like aggregates. However, little is known about how they form α-Syn aggregates from fibril seeds. Here, we developed an assay to study the process of aggregate formation using fluorescent protein-tagged α-Syn-expressing cells and examined the aggregate forming activity of exogenous α-Syn fibrils. α-Syn fibril-induced formation of intracellular aggregates was suppressed by a cathepsin B specific inhibitor, but not by a cathepsin D inhibitor. α-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 α-Syn fibrils. |
topic |
α-Synuclein Fibril Aggregate formation Cathepsin B Lysosome |
url |
http://www.sciencedirect.com/science/article/pii/S0969996114003040 |
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