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Back to the future: the 'old-fashioned' way to new medications for neurodegeneration

Nature Medicine volume 10, pages S51–S57 (2004)Cite this article

Abstract

Despite the increasing prevalence of Alzheimer's disease, Parkinson's disease and less common neurodegenerative diseases—and despite the large amount of primary research that has been carried out into the causes and pathogenic features of these conditions—progress toward effective treatments has been remarkably slow. Why is this, and what can be done to accelerate it? There are a number of obstacles to effective drug discovery for neurodegeneration, but by considering these problems it is possible to identify lessons for the future.

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Figure 1: Evolution of the pathway from studies of a human disease to trials of a candidate therapeutic agent.
Figure 2: The clinical effect of many drugs could result from a combination of molecular events.

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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).

    Article  CAS  Google Scholar 

  2. Caughey, B. & Lansbury, P.T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).

    Article  CAS  Google Scholar 

  3. Cohen, F.E. & Kelly, J.W. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003).

    Article  CAS  Google Scholar 

  4. Lansbury, P.T., Jr. & Brice, A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr. Opin. Cell Biol. 14, 653–660 (2002).

    Article  CAS  Google Scholar 

  5. Selkoe, D.J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).

    Article  CAS  Google Scholar 

  6. Dawson, T.M. & Dawson, V.L. Rare genetic mutations shed light on the pathogenesis of Parkinson disease. J. Clin. Invest. 111, 145–151 (2003).

    Article  CAS  Google Scholar 

  7. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).

    Article  CAS  Google Scholar 

  8. Kosaka, K. & Iseki, E. Dementia with Lewy bodies. Curr. Opin. Neurol. 9, 271–275 (1996).

    Article  CAS  Google Scholar 

  9. Karlawish, J.H. & Clark, C.M. Diagnostic evaluation of elderly patients with mild memory problems. Ann. Intern. Med. 138, 411–419 (2003).

    Article  Google Scholar 

  10. Maraganore, D.M. et al. Case-control study of the ubiquitin carboxy-terminal hydrolase L1 gene in Parkinson's disease. Neurology 53, 1858–1860 (1999).

    Article  CAS  Google Scholar 

  11. Satoh, J. & Kuroda, Y. A polymorphic variation of serine to tyrosine at codon 18 in the ubiquitin C-terminal hydrolase-L1 gene is associated with a reduced risk of sporadic Parkinson's disease in a Japanese population. J. Neurol. Sci. 189, 113–117 (2001).

    Article  CAS  Google Scholar 

  12. Wang, J. et al. ACT and UCH-L1 polymorphisms in Parkinson's disease and age of onset. Mov. Disord. 17, 767–771 (2002).

    Article  Google Scholar 

  13. Momose, Y. et al. Association studies of multiple candidate genes for Parkinson's disease using single nucleotide polymorphisms. Ann. Neurol. 51, 133–136 (2002).

    Article  CAS  Google Scholar 

  14. Maraganore, D.M. et al. Complex interactions in Parkinson's disease: a two-phased approach. Mov. Disord. 18, 631–636 (2003).

    Article  Google Scholar 

  15. Group, P.S. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 287, 1653–1661 (2002).

    Article  Google Scholar 

  16. Schapira, A.H. & Olanow, C.W. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 291, 358–364 (2004).

    Article  CAS  Google Scholar 

  17. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  18. Shorter, E. Looking backwards: a possible new path for drug discovery in psychopharmacology. Nat. Rev. Drug Discov. 1, 1003–1006 (2002).

    Article  CAS  Google Scholar 

  19. Berger, E. et al. A common origin for cosmic explosions inferred from calorimetry of GRB030329. Nature 426, 154–157 (2003).

    Article  CAS  Google Scholar 

  20. Yuan, J. & Yankner, B.A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).

    Article  CAS  Google Scholar 

  21. Cookson, M.R. Pathways to parkinsonism. Neuron 37, 7–10 (2003).

    Article  CAS  Google Scholar 

  22. Cai, X.D., Golde, T.E. & Younkin, S.G. Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science 259, 514–516 (1993).

    Article  CAS  Google Scholar 

  23. Citron, M. et al. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production. Nature 360, 672–674 (1992).

    Article  CAS  Google Scholar 

  24. Vassar, R. et al. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    Article  CAS  Google Scholar 

  25. Wolfe, M.S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999).

    Article  CAS  Google Scholar 

  26. McGeer, P.L., McGeer, E., Rogers, J. & Sibley, J. Anti-inflammatory drugs and Alzheimer disease. Lancet 335, 1037 (1990).

    Article  CAS  Google Scholar 

  27. Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212–216 (2001).

    Article  CAS  Google Scholar 

  28. Sagi, S.A., Weggen, S., Eriksen, J., Golde, T.E. & Koo, E.H. The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of κB kinase, and NF-κB, do not reduce amyloid β42 production. J. Biol. Chem. 278, 31825–31830 (2003).

    Article  CAS  Google Scholar 

  29. Zhou, Y. et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302, 1215–1217 (2003).

    Article  CAS  Google Scholar 

  30. Esler, W.P. & Wolfe, M.S. A portrait of Alzheimer secretases—new features and familiar faces. Science 293, 1449–1454 (2001).

    Article  CAS  Google Scholar 

  31. Nass, R., Hall, D.H., Miller, D.M., 3rd & Blakely, R.D. Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 99, 3264–3269 (2002).

    Article  CAS  Google Scholar 

  32. Feany, M.B. & Bender, W.W. A Drosophila model of Parkinson's disease. Nature 404, 394–398 (2000).

    Article  CAS  Google Scholar 

  33. Iijima, K. et al. Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila: a potential model for Alzheimer's disease. Proc. Natl. Acad. Sci. USA 101, 6623–6628 (2004).

    Article  CAS  Google Scholar 

  34. Auluck, P.K. & Bonini, N.M. Pharmacological prevention of Parkinson disease in Drosophila. Nat. Med. 8, 1185–1186 (2002).

    Article  CAS  Google Scholar 

  35. Steffan, J.S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001).

    Article  CAS  Google Scholar 

  36. Micchelli, C.A. et al. γ-Secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila. FASEB J. 17, 79–81 (2003).

    Article  CAS  Google Scholar 

  37. Borisy, A.A. et al. Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. USA 100, 7977–7982 (2003).

    Article  CAS  Google Scholar 

  38. Alper, J. Drug development. Biotech thinking comes to academic medical centers. Science 299, 1303–1305 (2003).

    Article  CAS  Google Scholar 

  39. Stein, R.L. A new model for drug discovery—meeting our societal obligation. Drug Discov. Today 8, 245–248 (2003).

    Article  Google Scholar 

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Authors and Affiliations

  1. Jr. is at the Harvard Center for Neurodegeneration and Repair and the Department of Neurology, Harvard Medical School, Center for Neurologic Diseases, Brigham and Women's Hospital, 65 Landsdowne St., Cambridge, 02139, Massachusetts, USA

    Peter T Lansbury Jr.

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  1. Peter T Lansbury Jr.
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Lansbury, P. Back to the future: the 'old-fashioned' way to new medications for neurodegeneration. Nat Med 10 (Suppl 7), S51–S57 (2004). https://doi.org/10.1038/nrn1435

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