ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons.

Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

FEBS letters 2013 May 2

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Kufor-Rakeb syndrome (KRS) was originally described as an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia. ATP13A2 was identified as the causative gene in KRS. ATP13A2 encodes the ATP13A2 protein, which is a lysosomal type5 P-type ATPase, and ATP13A2 mutations are linked to autosomal recessive familial parkinsonism. 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. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Citation

Hideaki Matsui, Fumiaki Sato, Shigeto Sato, Masato Koike, Yosuke Taruno, Shinji Saiki, Manabu Funayama, Hidefumi Ito, Yoshihito Taniguchi, Norihito Uemura, Atsushi Toyoda, Yoshiyuki Sakaki, Shunichi Takeda, Yasuo Uchiyama, Nobutaka Hattori, Ryosuke Takahashi. ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons. FEBS letters. 2013 May 2;587(9):1316-25