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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Abstract

Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

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Figure 1: Genetic studies of family 1.
Figure 2: Amino-acid sequence of Parkin protein.
Figure 3: Amino-acid sequence homology between Parkin and the ubiquitin family proteins.
Figure 4: Genetic studies of family 2.
Figure 5: Northern blot analysis of parkin gene expression.

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References

  1. Parkinson, J. An Essay on the Shaking Palsy(Whittingham and Rowland, London, (1817).

    Google Scholar 

  2. Yamamura, Y., Arihiro, K., Kohriyama, T. & Nakamura, S. Early-onset parkinsonism with diurnal fluctuation-clinical and pathological studies. Clin. Neurol. (Tokyo) 33, 491–496 (1993).

    CAS  Google Scholar 

  3. Ishikawa, A. & Tsuji, S. Clinical analysis of 17 patients in 12 Japanese families with autosomal recessive type juvenile parkinsonism. Neurology 47, 160–166 (1996).

    Article  CAS  Google Scholar 

  4. Matsumine, H.et al. Localization of a gene for autosomal recessive form of juvenile parkinsonism (AR-JP) to chromosome 6q25.2-27. Am. J. Hum. Genet. 60, 588–596 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Matsumine, H.et al. Evidence for a microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonismin (AR-JP). Genomics(in the press).

  6. Asakawa, S.et al. Human BAC library: Construction and rapid screening. Gene 191, 69–79 (1997).

    Article  CAS  Google Scholar 

  7. Finley, D. & Chau, V. Ubiquitination. Annu. Rev. Biol. 7, 25–69 (1991).

    Article  CAS  Google Scholar 

  8. Saurin, A. J., Borden, K. L. B., Boddy, M. N. & Freemont, P. S. Does this have a familiar RING? Trends Biochem. Sci. 21, 208–214 (1996).

    Article  CAS  Google Scholar 

  9. Aasland, R., Gibson, T. J. & Stewart, A. F. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem. Sci. 20, 56–59 (1996).

    Article  Google Scholar 

  10. Takahashi, H.et al. Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44, 437–441 (1994).

    Article  CAS  Google Scholar 

  11. Calne, D. B. & Langston, J. W. Aetiology of Parkinson's disease. Lancet ii, 1457–1459 (1983).

    Article  Google Scholar 

  12. Jenner, P., Schapira, A. H. V. & Marsden, C. D. New insights into the cause of Parkinson's disease. Neurology 42, 2241–2250 (1992).

    Article  CAS  Google Scholar 

  13. Schapira, A. H. V.et al. Mitochondrial complex I deficiency in Parkinson's disease. J. Neurochem. 54, 823–827 (1990).

    Article  CAS  Google Scholar 

  14. Mizuno, Y.et al. Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. Biochim. Biophys. Acta 1271, 265–274 (1995).

    Article  Google Scholar 

  15. Spillantini, M. G.et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    Article  ADS  CAS  Google Scholar 

  16. Polymeropoulos, M. H.et al. Mutation in α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    Article  CAS  Google Scholar 

  17. Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 1641–1644 (1987).

    Article  ADS  CAS  Google Scholar 

  18. Morishima-Kawashima, M.et al. Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron 10, 1151–1160 (1993).

    Article  CAS  Google Scholar 

  19. Gregori, L., Fuchs, C., Figueiredo-Pereira, M. E., Nostrand, W. E. V. & Goldgaber, D. Amyloid β-protein inhibits ubiquitin-dependent protein degradation in vitro. J. Biol. Chem. 270, 19702–19708 (1995).

    Article  CAS  Google Scholar 

  20. Love, S., Saitoh, T., Quijada, S., Cole, G. M. & Terry, R. D. Alz-50, ubiquitin and Tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J. Neuropathol. Exp. Neurol. 47, 393–405 (1988).

    Article  CAS  Google Scholar 

  21. Galloway, P. G., Mulvihill, O. & Perry, G. Filaments of Lewy bodies contain insoluble cytoskeletal elements. Am. J. Pathol. 140, 809–822 (1922).

    Google Scholar 

  22. Iwatsubo, T.et al. Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am. J. Pathol. 148, 1517–1529 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ciechanover, A. The ubiquitin-proteasome proteolytic pathway. Cell 79, 13–21 (1994).

    Article  CAS  Google Scholar 

  24. Hochstrasser, M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr. Opin. Cell Biol. 7, 215–223 (1995).

    Article  CAS  Google Scholar 

  25. Gregori, L., Poosch, M. S., Cousins, G. & Chau, V. Auniform isopeptide-linked multiubiquitin chain is sufficient to target substrate for degradation in ubiquitin-mediated proteolysis. J. Biol. Chem. 265, 8354–8357 (1990).

    CAS  PubMed  Google Scholar 

  26. Finley, D., Bartel, B. & Varshavsky, A. The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis. Nature 338, 394–401 (1989).

    Article  ADS  CAS  Google Scholar 

  27. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual(Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, (1989).

    Google Scholar 

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Acknowledgements

We thank the four AR-JP families for blood samples, K. Nagamine and J. Kudoh for discussions, H. Harigai for assistance in manuscript preparation, and T. Tamura and Y. Shimizu for technical advice. This study was supported by the Ministry of Education, Science, Sports and Culture, Japan, and by the National Parkinson Foundation.

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Correspondence to Nobuyoshi Shimizu.

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Kitada, T., Asakawa, S., Hattori, N. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998). https://doi.org/10.1038/33416

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