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ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint‐like inclusion body formation, and selective degeneration of dopaminergic neurons
Author(s) -
Matsui Hideaki,
Sato Fumiaki,
Sato Shigeto,
Koike Masato,
Taruno Yosuke,
Saiki Shinji,
Funayama Manabu,
Ito Hidefumi,
Taniguchi Yoshihito,
Uemura Norihito,
Toyoda Atsushi,
Sakaki Yoshiyuki,
Takeda Shunichi,
Uchiyama Yasuo,
Hattori Nobutaka,
Takahashi Ryosuke
Publication year - 2013
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2013.02.046
Subject(s) - dopaminergic , lysosome , parkinsonism , cathepsin d , biology , endoplasmic reticulum , neurotoxicity , microbiology and biotechnology , medicine , endocrinology , dopamine , biochemistry , disease , toxicity , enzyme
Here, we report that normal ATP13A2 localizes in the lysosome, whereas disease‐associated variants remain in the endoplasmic reticulum. Cathepsin D activity was decreased in ATP13A2‐knockdown cells that displayed lysosome‐like bodies characterized by fingerprint‐like structures. Furthermore, an atp13a2 mutation in medaka fish resulted in dopaminergic neuronal death, decreased cathepsin D activity, and fingerprint‐like structures in the brain. Based on these results, lysosome abnormality is very likely to be the primary cause of KRS/PARK9.