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FEBS Lett. 2013 May 2;587(9):1316-25. doi: 10.1016/j.febslet.2013.02.046. Epub 2013 Mar 13.

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

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  • 1Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.


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.

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