Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders1. 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 diseases2. 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 system3,4,5,6. 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 syndrome7,8). 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 specificity9 to the protein networks implicated in neurodegeneration and parkinsonism.
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We thank E. Erxlebe and A. Cardenas for technical assistance, D. Isbrandt for help with the Agilent analysis and the families for their cooperation. Human brain samples were obtained from BrainNet (GA28). The antibody to H4B4 was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development (NICHD) and maintained by The University of Iowa Department of Biological Sciences. This study was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG) to C.K. and grants from the Royal Society, the Bundesministerium für Bildung und Forschung (BMBF) (NGFN-2) and the Hertie Foundation to B.L. and J.R. C.G.W. is supported by the Wellcome Trust. CECS is a Millennium Science Institute and is funded in part by grants from Fundación Andes, the Tinker Foundation and Empresas Compañía Manufacturera de Papeles y Cartones (CMPC).
The authors declare no competing financial interests.
RNA quality and ATP13A2 mRNA levels in brain samples. (PDF 16 kb)
Control hybridization of RNA (northern) blot and dot blot membranes with β-actin. (PDF 440 kb)
Localization of tissues on the dot blot membrane. (PDF 285 kb)
Two-point lod scores for microsatellites in the Kufor-Rakeb region. (PDF 86 kb)
Primer sequences. (PDF 25 kb)
Features of human post-mortem midbrain samples. (PDF 16 kb)
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Ramirez, A., Heimbach, A., Gründemann, J. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38, 1184–1191 (2006). https://doi.org/10.1038/ng1884
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