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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 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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Figure 1: Haplotype analysis of the KRS-locus on chromosome 1p in the Chilean family.
Figure 2: ATP13A2 mutations in individuals with KRS and their predicted effect on the protein structure.
Figure 3: Expression analysis of ATP13A2.
Figure 4: Expression analysis of ATP13A2 mRNA levels in post-mortem brain samples of patients with idiopathic Parkinson disease and control individuals.
Figure 5: Subcellular localization of ATP13A2-WT and KRS-mutants in transiently transfected COS7 cells by immunofluorescence.
Figure 6: Protein blot analysis of ATP13A2 WT and mutant V5-tagged constructs in transiently transfected COS7 cells.

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References

  1. Nussbaum, R.L. & Ellis, C.E. Alzheimer's disease and Parkinson's disease. N. Engl. J. Med. 348, 1356–1364 (2003).

    CAS  Article  Google Scholar 

  2. Vila, M. & Przedborski, S. Genetic clues to the pathogenesis of Parkinson's disease. Nat. Med. 10 (Suppl.), S58–S62 (2004).

    Article  Google Scholar 

  3. Ciechanover, A. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat. Rev. Mol. Cell Biol. 6, 79–87 (2005).

    CAS  Article  Google Scholar 

  4. Cookson, M.R. The biochemistry of Parkinson's disease. Annu. Rev. Biochem. 74, 29–52 (2005).

    CAS  Article  Google Scholar 

  5. Dawson, T.M. & Dawson, V.L. Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819–822 (2003).

    CAS  Article  Google Scholar 

  6. Selkoe, D.J. Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat. Cell Biol. 6, 1054–1061 (2004).

    CAS  Article  Google Scholar 

  7. Najim al-Din, A.S., Wriekat, A., Mubaidin, A., Dasouki, M. & Hiari, M. Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol. Scand. 89, 347–352 (1994).

    CAS  Article  Google Scholar 

  8. Williams, D.R., Hadeed, A., Al-Din, A.S., Wreikat, A.L. & Lees, A.J. Kufor Rakeb Disease: Autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov. Disord. 20, 1264–1271 (2005).

    Article  Google Scholar 

  9. Axelsen, K.B. & Palmgren, M.G. Evolution of substrate specificities in the P-type ATPase superfamily. J. Mol. Evol. 46, 84–101 (1998).

    CAS  Article  Google Scholar 

  10. Hampshire, D.J. et al. Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. J. Med. Genet. 38, 680–682 (2001).

    CAS  Article  Google Scholar 

  11. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    CAS  Article  Google Scholar 

  12. Bonifati, V. et al. DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol. Sci. 24, 159–160 (2003).

    CAS  Article  Google Scholar 

  13. Valente, E.M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    CAS  Article  Google Scholar 

  14. Kuhlbrandt, W. Biology, structure and mechanism of P-type ATPases. Nat. Rev. Mol. Cell Biol. 5, 282–295 (2004).

    Article  Google Scholar 

  15. Schultheis, P.J. et al. Characterization of the P5 subfamily of P-type transport ATPases in mice. Biochem. Biophys. Res. Commun. 323, 731–738 (2004).

    CAS  Article  Google Scholar 

  16. Kwasnicka-Crawford, D.A. et al. Characterization of a novel cation transporter ATPase gene (ATP13A4) interrupted by 3q25-q29 inversion in an individual with language delay. Genomics 86, 182–194 (2005).

    CAS  Article  Google Scholar 

  17. Liss, B., Neu, A. & Roeper, J. The weaver mouse gain-of-function phenotype of dopaminergic midbrain neurons is determined by coactivation of wvGirk2 and K-ATP channels. J. Neurosci. 19, 8839–8848 (1999).

    CAS  Article  Google Scholar 

  18. Liss, B. et al. Tuning pacemaker frequency of individual dopaminergic neurons by Kv4.3L and KChip3.1 transcription. EMBO J. 20, 5715–5724 (2001).

    CAS  Article  Google Scholar 

  19. Liss, B. Improved quantitative real-time RT-PCR for expression profiling of individual cells. Nucleic Acids Res. 30, e89 (2002).

    Article  Google Scholar 

  20. Schroeder, A. et al. The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol. Biol. 7, 3 (2006).

    Article  Google Scholar 

  21. Rao, R.V. & Bredesen, D.E. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr. Opin. Cell Biol. 16, 653–662 (2004).

    CAS  Article  Google Scholar 

  22. Murakami, Y. et al. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360, 597–599 (1992).

    CAS  Article  Google Scholar 

  23. Hoyt, M.A. & Coffino, P. Ubiquitin-free routes into the proteasome. Cell. Mol. Life Sci. 61, 1596–1600 (2004).

    CAS  Article  Google Scholar 

  24. Lee, H.J., Khoshaghideh, F., Patel, S. & Lee, S.J. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 24, 1888–1896 (2004).

    CAS  Article  Google Scholar 

  25. Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. & Rubinsztein, D.C. α-synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).

    CAS  Article  Google Scholar 

  26. Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    CAS  Article  Google Scholar 

  27. Aharon-Peretz, J., Rosenbaum, H. & Gershoni-Baruch, R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972–1977 (2004).

    CAS  Article  Google Scholar 

  28. Goker-Alpan, O. et al. Parkinsonism among Gaucher disease carriers. J. Med. Genet. 41, 937–940 (2004).

    CAS  Article  Google Scholar 

  29. Auer, H. et al. Chipping away at the chip bias: RNA degradation in microarray analysis. Nat. Genet. 35, 292–293 (2003).

    CAS  Article  Google Scholar 

  30. Imbeaud, S. et al. Towards standardization of RNA quality assessment using user-independent classifiers of microcapillary electrophoresis traces. Nucleic Acids Res. 33, e56 (2005).

    Article  Google Scholar 

Download references

Acknowledgements

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).

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Correspondence to Christian Kubisch.

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Supplementary information

Supplementary Fig. 1

RNA quality and ATP13A2 mRNA levels in brain samples. (PDF 16 kb)

Supplementary Fig. 2

Control hybridization of RNA (northern) blot and dot blot membranes with β-actin. (PDF 440 kb)

Supplementary Fig. 3

Localization of tissues on the dot blot membrane. (PDF 285 kb)

Supplementary Table 1

Two-point lod scores for microsatellites in the Kufor-Rakeb region. (PDF 86 kb)

Supplementary Table 2

Primer sequences. (PDF 25 kb)

Supplementary Table 3

Features of human post-mortem midbrain samples. (PDF 16 kb)

Supplementary Note (PDF 39 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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