ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons
ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons
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DOI：
10.1016/j.febslet.2013.02.046
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发表时间：
2013-05-02
期刊：
影响因子：
3.5
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Matsui, Hideaki;Sato, Fumiaki;Takahashi, Ryosuke
Kufor-Rakeb综合征（KRS）最初被描述为一种常染色体隐性遗传形式的早发性帕金森综合征，伴有锥体细胞变性和痴呆。KRS的致病基因为ATP 13 A2。ATP 13 A2编码ATP 13 A2蛋白，它是一种溶酶体5型P型ATP酶，ATP 13 A2突变与常染色体隐性遗传家族性帕金森综合征有关。组织蛋白酶D活性降低ATP 13 A2敲除细胞，显示溶酶体样机构的特征在于指纹样结构。此外，青鳉鱼的atp 13 a2突变导致多巴胺能神经元死亡，组织蛋白酶D活性降低，大脑中出现指纹样结构。根据这些结果，溶酶体异常很可能是KRS/PARK 9的主要原因。(C)2013年欧洲生物化学学会联合会。由Elsevier B出版。V.保留所有权利。
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.