Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.
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.
Ramirez
Alfredo
A
Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
Heimbach
André
A
Gründemann
Jan
J
Stiller
Barbara
B
Hampshire
Dan
D
Cid
L Pablo
LP
Goebel
Ingrid
I
Mubaidin
Ammar F
AF
Wriekat
Abdul-Latif
AL
Roeper
Jochen
J
Al-Din
Amir
A
Hillmer
Axel M
AM
Karsak
Meliha
M
Liss
Birgit
B
Woods
C Geoffrey
CG
Behrens
Maria I
MI
Kubisch
Christian
C
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*
C514983:ATP13A2 protein, human; D000251:Adenosine Triphosphatases; D006180:Proton-Translocating ATPases