title: Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism.
abstract: Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS.
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Prachi
authors.initials: P
authors.lastname: Mehta
authors.forename: Antony A
authors.initials: AA
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Veivers
authors.forename: André
authors.initials: A
authors.lastname: Heimbach
authors.forename: Barbara
authors.initials: B
authors.lastname: Stiller
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Victor S
authors.initials: VS
authors.lastname: Fung
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay-Sim
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D021381:Protein Transport / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism*; D020871:RNA Stability; D016415:Sequence Alignment; D013312:Stress, Physiological / Q000235:genetics; D055815:Young Adult
chemical_list: C514983:ATP13A2 protein, human; D006180:Proton-Translocating ATPases