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

被引：58

作者：

Matsui, Hideaki ^{[1
,7
]}

Sato, Fumiaki ^{[2
,7
]}

Sato, Shigeto ^{[2
,7
]}

Koike, Masato ^{[6
]}

Taruno, Yosuke ^{[1
,7
]}

Saiki, Shinji ^{[2
,7
]}

Funayama, Manabu ^{[4
,7
]}

Ito, Hidefumi ^{[1
,7
]}

Taniguchi, Yoshihito ^{[3
,7
]}

Uemura, Norihito ^{[1
,7
]}

Toyoda, Atsushi ^{[5
]}

Sakaki, Yoshiyuki ^{[5
]}

Takeda, Shunichi ^{[3
,7
]}

Uchiyama, Yasuo ^{[6
]}

Hattori, Nobutaka ^{[2
,7
]}

Takahashi, Ryosuke ^{[1
,7
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto 6068507, Japan

[2] Juntendo Univ, Sch Med, Dept Neurol, Bunkyo Ku, Tokyo 1138421, Japan

[3] Kyoto Univ, Dept Radiat Genet, Grad Sch Med, Kyoto 6068501, Japan

[4] Juntendo Univ, Sch Med, Res Inst Dis Old Age, Bunkyo Ku, Tokyo 1138421, Japan

[5] RIKEN Genom Sci Ctr, Yokohama, Kanagawa 2300045, Japan

[6] Juntendo Univ, Sch Med, Dept Cell Biol & Neurosci, Bunkyo Ku, Tokyo 1138421, Japan

[7] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan

来源：

FEBS LETTERS | 2013年 / 587卷 / 09期

关键词：

Parkinson's disease; Medaka fish; ATP13A2; Lysosome; KUFOR-RAKEB SYNDROME; P-TYPE ATPASE; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; CEROID-LIPOFUSCINOSIS; MUTATIONS; STORAGE; NEUROTOXICITY; HOMEOSTASIS; PROTEASOME;

D O I：

10.1016/j.febslet.2013.02.046

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

引用

页码：1316 / 1325

页数：10

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