title: Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.
abstract: Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.forename: André
authors.initials: A
authors.lastname: Heimbach
authors.forename: Jan
authors.initials: J
authors.lastname: Gründemann
authors.forename: Barbara
authors.initials: B
authors.lastname: Stiller
authors.forename: Dan
authors.initials: D
authors.lastname: Hampshire
authors.forename: L Pablo
authors.initials: LP
authors.lastname: Cid
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.forename: Ammar F
authors.initials: AF
authors.lastname: Mubaidin
authors.forename: Abdul-Latif
authors.initials: AL
authors.lastname: Wriekat
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
authors.forename: Amir
authors.initials: A
authors.lastname: Al-Din
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
authors.forename: Meliha
authors.initials: M
authors.lastname: Karsak
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Maria I
authors.initials: MI
authors.lastname: Behrens
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D003704:Dementia / Q000209:etiology* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D008636:Mesencephalon / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C514983:ATP13A2 protein, human; D000251:Adenosine Triphosphatases; D006180:Proton-Translocating ATPases