title: ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons.
abstract: 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.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsui
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sato
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Taruno
authors.forename: Shinji
authors.initials: S
authors.lastname: Saiki
authors.forename: Manabu
authors.initials: M
authors.lastname: Funayama
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Norihito
authors.initials: N
authors.lastname: Uemura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyoda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakaki
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000378:metabolism*; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000201:enzymology / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D009990:Oryzias / Q000235:genetics; D021381:Protein Transport; D006180:Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics*
chemical_list: C514983:ATP13A2 protein, human; D002402:Cathepsin D; D006180:Proton-Translocating ATPases