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Neuroprotective and neurorestorative strategies for Parkinson's disease

Nature Neuroscience volume 5, pages 1058–1061 (2002)Cite this article

Abstract

Advances in understanding the molecular mechanisms of cell death and the pathogenesis of sporadic and familial Parkinson's disease are creating new opportunities for the development of neuroprotective and/or neurorestorative therapies. Here we review many of these advances, highlighting areas and strategies that might be particularly suited to the development of innovative approaches that prevent degeneration and/or restore function in Parkinson's disease.

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Figure 1: Potential neuroprotective strategies against mitochondrial complex 1 inhibition.
Figure 2: Potential neuroprotective strategies against α-synuclein toxicity and loss of parkin function.
Figure 3: Potential neurorestorative therapies for PD.

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References

  1. Lang, A.E. & Lozano, A.M. Parkinson's disease. First of two parts. N. Engl. J. Med. 339, 1044–1053 (1998).

    Article  CAS  Google Scholar 

  2. Lang, A.E. & Lozano, A.M. Parkinson's disease. Second of two parts. N. Engl. J. Med. 339, 1130–1143 (1998).

    Article  CAS  Google Scholar 

  3. Dawson, T.M., Mandir, A.S. & Lee, M.K. Animal models of PD: pieces of the same puzzle? Neuron 35, 219–222 (2002).

    Article  CAS  Google Scholar 

  4. Mizuno, Y., Hattori, N., Mori, H., Suzuki, T. & Tanaka, K. Parkin and Parkinson's disease. Curr. Opin. Neurol. 14, 477–482 (2001).

    Article  CAS  Google Scholar 

  5. Polymeropoulos, M.H. Genetics of Parkinson's disease. Ann. NY Acad. Sci. 920, 28–32 (2000).

    Article  CAS  Google Scholar 

  6. Dunnett, S.B. & Bjorklund, A. Prospects for new restorative and neuroprotective treatments in Parkinson's disease. Nature 399, A32–A39 (1999).

    Article  CAS  Google Scholar 

  7. Chung, K.K., Dawson, V.L. & Dawson, T.M. The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci. 24 (Suppl.), S7–S14 (2001).

    Article  CAS  Google Scholar 

  8. Lavedan, C., Buchholtz, S., Nussbaum, R.L., Albin, R.L. & Polymeropoulos, M.H. A mutation in the human neurofilament M gene in Parkinson's disease that suggests a role for the cytoskeleton in neuronal degeneration. Neurosci. Lett. 322, 57–61 (2002).

    Article  CAS  Google Scholar 

  9. Trojanowski, J.Q., Goedert, M., Iwatsubo, T. & Lee, V.M. Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia. Cell Death Differ. 5, 832–837 (1998).

    Article  CAS  Google Scholar 

  10. Zhang, Y., Dawson, V.L. & Dawson, T.M. Oxidative stress and genetics in the pathogenesis of Parkinson's disease. Neurobiol. Dis. 7, 240–250 (2000).

    Article  CAS  Google Scholar 

  11. Beal, M.F. Experimental models of Parkinson's disease. Nat. Rev. Neurosci. 2, 325–334 (2001).

    Article  CAS  Google Scholar 

  12. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301–1306 (2000).

    Article  CAS  Google Scholar 

  13. Goedert, M. Alpha-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2, 492–501 (2001).

    Article  CAS  Google Scholar 

  14. Galvin, J.E., Lee, V.M. & Trojanowski, J.Q. Synucleinopathies: clinical and pathological implications. Arch. Neurol. 58, 186–190 (2001).

    Article  CAS  Google Scholar 

  15. Xu, J. et al. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat. Med. 8, 600–606 (2002).

    Article  CAS  Google Scholar 

  16. Lansbury, P.T. & Brice, A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr. Opin. Genet. Dev. 12, 299–306 (2002).

    Article  CAS  Google Scholar 

  17. Conway, K.A., Rochet, J.C., Bieganski, R.M. & Lansbury, P.T. Jr. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294, 1346–1349 (2001).

    Article  CAS  Google Scholar 

  18. Hashimoto, M., Rockenstein, E., Mante, M., Mallory, M. & Masliah, E. Beta-synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32, 213–223 (2001).

    Article  CAS  Google Scholar 

  19. Uversky, V.N. et al. Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J. Biol. Chem. 277, 11970–11978 (2002).

    Article  CAS  Google Scholar 

  20. Auluck, P.K., Chan, H.Y., Trojanowski, J.Q., Lee, V.M. & Bonini, N.M. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865–868 (2002).

    Article  CAS  Google Scholar 

  21. Muqit, M.M. & Feany, M.B. Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nat. Rev. Neurosci. 3, 237–243 (2002).

    Article  CAS  Google Scholar 

  22. Lee, M.K. et al. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53-Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc. Natl. Acad. Sci. USA 99, 8968–8973 (2002).

    Article  CAS  Google Scholar 

  23. Wolfe, M.S. Secretase as a target for Alzheimer's disease. Curr. Top. Med. Chem. 2, 371–383 (2002).

    Article  CAS  Google Scholar 

  24. Fujiwara, H. et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).

    Article  CAS  Google Scholar 

  25. Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902 (2001).

    Article  CAS  Google Scholar 

  26. Gash, D.M., Zhang, Z. & Gerhardt, G. Neuroprotective and neurorestorative properties of GDNF. Ann. Neurol. 44, S121–S125 (1998).

    Article  CAS  Google Scholar 

  27. Kordower, J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767–773 (2000).

    Article  CAS  Google Scholar 

  28. Bjorklund, A. & Lindvall, O. Parkinson disease gene therapy moves toward the clinic. Nat. Med. 6, 1207–1208 (2000).

    Article  CAS  Google Scholar 

  29. Mayor, S. New treatment improves symptoms of Parkinson's disease. BMJ 324, 997 (2002).

    Article  Google Scholar 

  30. Date, I. et al. Grafting of encapsulated genetically modified cells secreting GDNF into the striatum of parkinsonian model rats. Cell Transplant. 10, 397–401 (2001).

    Article  CAS  Google Scholar 

  31. McKay, R. Building animals from stem cells. Ann. NY Acad. Sci. 961, 44 (2002).

    Article  Google Scholar 

  32. Rossi, F. & Cattaneo, E. Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat. Rev. Neurosci. 3, 401–409 (2002).

    Article  CAS  Google Scholar 

  33. Dunnett, S.B., Bjorklund, A. & Lindvall, O. Cell therapy in Parkinson's disease—stop or go? Nat. Rev. Neurosci. 2, 365–369 (2001).

    Article  CAS  Google Scholar 

  34. Bjorklund, L.M. et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl. Acad. Sci. USA 99, 2344–2349 (2002).

    Article  CAS  Google Scholar 

  35. Kim, J.H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge the secretarial assistance of Weza Cotman. This work was supported by the National Institutes of Health, the Department of Defense and the Edward and Anna D. Mitchell Family Foundation. We apologize to our colleagues whose work was not discussed in detail or referenced due to space limitations.

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Authors and Affiliations

  1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Ted M. Dawson & Valina L. Dawson

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Ted M. Dawson & Valina L. Dawson

  3. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Ted M. Dawson & Valina L. Dawson

  4. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Valina L. Dawson

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  1. Ted M. Dawson
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  2. Valina L. Dawson
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Correspondence to Ted M. Dawson.

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Dawson, T., Dawson, V. Neuroprotective and neurorestorative strategies for Parkinson's disease. Nat Neurosci 5 (Suppl 11), 1058–1061 (2002). https://doi.org/10.1038/nn941

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