Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cell death in the nervous system

Abstract

Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease trigger neuronal cell death through endogenous suicide pathways. Surprisingly, although the cell death itself may occur relatively late in the course of the degenerative process, the mediators of the underlying cell-death pathways have shown promise as potential therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Misfolded proteins and endoplasmic-reticulum stress.
Figure 2: Caspase cleavage in Alzheimer's disease.

Similar content being viewed by others

References

  1. Studnicka, F. K. in Lehrbuch der vergleichende mikroskopischen Anatomie der Wirbeltiere (ed. Oppel, A.) 1–256 (Fischer, Germany, 1905).

    Google Scholar 

  2. Levi-Montalcini, R. The nerve growth factor: its mode of action on sensory and sympathetic nerve cells. Harvey Lect. 60, 217–259 (1966).

    CAS  PubMed  Google Scholar 

  3. Lockshin, R. A. & Williams, C. M. Programmed cell death. II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J. Insect Physiol. 10, 643–649 (1964).

    Article  CAS  Google Scholar 

  4. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    Article  CAS  Google Scholar 

  5. Clarke, P. G. Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. 181, 195–213 (1990).

    Article  CAS  Google Scholar 

  6. Cunningham, T. J. Naturally occurring neuron death and its regulation by developing neural pathways. Int. Rev. Cytol. 74, 163–186 (1982).

    Article  CAS  Google Scholar 

  7. Dal Canto, M. C. & Gurney, M. E. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am. J. Pathol. 145, 1271–1279 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Schweichel, J. U. & Merker, H. J. The morphology of various types of cell death in prenatal tissues. Teratology 7, 253–266 (1973).

    Article  CAS  Google Scholar 

  9. Sperandio, S., de Belle, I. & Bredesen, D. E. An alternative, non-apoptotic form of programmed cell death. Proc. Natl Acad. Sci. USA 97, 14376–14381 (2000).

    Article  ADS  CAS  Google Scholar 

  10. Oppenheim, R. W. Naturally occurring cell death during neural development. Trends Neurosci. 17, 487–493 (1985).

    Article  Google Scholar 

  11. Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992).

    CAS  PubMed  Google Scholar 

  12. Thornberry, N. A. & Lazebnik, Y. Caspases: enemies within. Science 281, 1312–1316 (1998).

    Article  CAS  Google Scholar 

  13. Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 75, 641–652 (1993).

    Article  CAS  Google Scholar 

  14. Salvesen, G. S. & Dixit, V. M. Caspases: intracellular signaling by proteolysis. Cell 91, 443–446 (1997).

    Article  CAS  Google Scholar 

  15. Morishima, N., Nakanishi, K., Takenouchi, H., Shibata, T. & Yasuhiko, Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J. Biol. Chem. 277, 34287–34294 (2002).

    Article  CAS  Google Scholar 

  16. Rao, R. V. et al. Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J. Biol. Chem. 277, 21836–21842 (2002).

    Article  CAS  Google Scholar 

  17. Yuan, J. & Yankner, B. A. Caspase activity sows the seeds of neuronal death. Nature Cell Biol. 1, E44–E45 (1999).

    Article  CAS  Google Scholar 

  18. Green, D. R. & Kroemer, G. Pharmacological manipulation of cell death: clinical applications in sight? J. Clin. Invest. 115, 2610–2617 (2005).

    Article  CAS  Google Scholar 

  19. Fuentes-Prior, P. & Salvesen, G. S. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem. J. 384, 201–232 (2004).

    Article  CAS  Google Scholar 

  20. Kopito, R. R. & Ron, D. Conformational disease. Nature Cell Biol. 2, E207–E209 (2000).

    Article  CAS  Google Scholar 

  21. Taylor, J. P., Hardy, J. & Fischbeck, K. H. Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002).

    Article  ADS  CAS  Google Scholar 

  22. Sitia, R. & Braakman, I. Quality control in the endoplasmic reticulum protein factory. Nature 426, 891–894 (2003).

    Article  ADS  CAS  Google Scholar 

  23. Sherman, M. Y. & Goldberg, A. L. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29, 15–32 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Scorrano, L. et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135–139 (2003).

    Article  ADS  CAS  Google Scholar 

  26. Ruiz-Vela, A., Opferman, J. T., Cheng, E. H. & Korsmeyer, S. J. Proapoptotic BAX and BAK control multiple initiator caspases. EMBO Rep. 6, 379–385 (2005).

    Article  CAS  Google Scholar 

  27. Chae, H. J. et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol. Cell 15, 355–366 (2004).

    Article  CAS  Google Scholar 

  28. Li, J., Lee, B. & Lee, A. S. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J. Biol. Chem. 281, 7260–7270 (2006).

    Article  CAS  Google Scholar 

  29. Hegde, R. S. et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).

    Article  ADS  CAS  Google Scholar 

  30. Levine, B. & Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679–2688 (2005).

    Article  CAS  Google Scholar 

  31. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    Article  CAS  Google Scholar 

  32. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    Article  ADS  CAS  Google Scholar 

  33. Shimizu, S. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol. 6, 1221–1228 (2004).

    Article  CAS  Google Scholar 

  34. Yu, L. et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004).

    Article  ADS  CAS  Google Scholar 

  35. Yu, L. et al. Autophagic programmed cell death by selective catalase degradation. Proc. Natl Acad. Sci. USA 103, 4952–4957 (2006).

    Article  ADS  CAS  Google Scholar 

  36. Gomez-Santos, C. et al. Dopamine induces autophagic cell death and α-synuclein increase in human neuroblastoma SH-SY5Y cells. J. Neurosci. Res. 73, 341–350 (2003).

    Article  CAS  Google Scholar 

  37. Hengartner, M. O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).

    Article  ADS  CAS  Google Scholar 

  38. Sperandio, S. et al. Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ. 11, 1066–1075 (2004).

    Article  CAS  Google Scholar 

  39. Koh, J. Y., Gwag, B. J., Lobner, D. & Choi, D. W. Potentiated necrosis of cultured cortical neurons by neurotrophins. Science 268, 573–575 (1995).

    Article  ADS  CAS  Google Scholar 

  40. Formigli, L. et al. Aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J. Cell Physiol. 182, 41–49 (2000).

    Article  CAS  Google Scholar 

  41. Ankarcrona, M. et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15, 961–973 (1995).

    Article  CAS  Google Scholar 

  42. Syntichaki, P., Xu, K., Driscoll, M. & Tavernarakis, N. Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419, 939–944 (2002).

    Article  ADS  CAS  Google Scholar 

  43. Yu, S. W. et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297, 259–263 (2002).

    Article  ADS  CAS  Google Scholar 

  44. Susin, S. A. et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999).

    Article  ADS  CAS  Google Scholar 

  45. Liu, X., Van Vleet, T. & Schnellmann, R. G. The role of calpain in oncotic cell death. Annu. Rev. Pharmacol. Toxicol. 44, 349–370 (2004).

    Article  CAS  Google Scholar 

  46. Galvan, V. et al. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc. Natl Acad. Sci. USA 103, 7130–7135 (2006).

    Article  ADS  CAS  Google Scholar 

  47. Graham, R. K. et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179–1191 (2006).

    Article  CAS  Google Scholar 

  48. Yang, F. et al. Antibody to caspase-cleaved actin detects apoptosis in differentiated neuroblastoma and plaque-associated neurons and microglia in Alzheimer's disease. Am. J. Pathol. 152, 379–389 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Friedlander, R. M., Brown, R. H., Gagliardini, V., Wang, J. & Yuan, J. Inhibition of ICE slows ALS in mice. Nature 388, 31 (1997).

    Article  ADS  CAS  Google Scholar 

  50. Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999).

    Article  ADS  CAS  Google Scholar 

  51. Kostic, V., Jackson-Lewis, V., de Bilbao, F., Dubois-Dauphin, M. & Przedborski, S. Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 277, 559–562 (1997).

    Article  CAS  Google Scholar 

  52. Friedlander, R. M. Apoptosis and caspases in neurodegenerative diseases. N. Engl. J. Med. 348, 1365–1375 (2003).

    Article  CAS  Google Scholar 

  53. Jin, K. et al. FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA 102, 18189–18194 (2005).

    Article  ADS  CAS  Google Scholar 

  54. Tuszynski, M. H. et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Med. 11, 551–555 (2005).

    Article  CAS  Google Scholar 

  55. Lang, A. E. et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459–466 (2006).

    Article  CAS  Google Scholar 

  56. Kordower, J. H., Isacson, O. & Emerich, D. F. Cellular delivery of trophic factors for the treatment of Huntington's disease: is neuroprotection possible? Exp. Neurol. 159, 4–20 (1999).

    Article  CAS  Google Scholar 

  57. Borrell-Pages, M. et al. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J. Clin. Invest. 116, 1410–1424 (2006).

    Article  CAS  Google Scholar 

  58. Kerr, J. F. R. & Harmon, B. V. in Apoptosis: The Molecular Basis of Cell Death (eds Tomei, L. D. & Cope, F. O.) 321 (Cold Spring Harbor Laboratory Press, Plainview, New York, 1991).

    Google Scholar 

  59. Bursch, W. et al. Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J. Cell Sci. 113, 1189–1198 (2000).

    CAS  PubMed  Google Scholar 

  60. Hall, I. H., Elkins, A. L., Karthikeyan, S. & Spielvogel, B. F. The cytotoxicity of 1-(phenylmethyl)-4,7,10-tris-[(4'methylphenyl) sulfonyl]-1,4,7,10-tetraazacyclododecane in human Tmolt3 T leukemic cells. Anticancer Res. 17, 1195–1198 (1997).

    CAS  PubMed  Google Scholar 

  61. Susin, S. A. et al. Two distinct pathways leading to nuclear apoptosis. J. Exp. Med. 192, 571–580 (2000).

    Article  ADS  CAS  Google Scholar 

  62. Ohno, M. et al. 'Apoptotic' myocytes in infarct area in rabbit hearts may be oncotic myocytes with DNA fragmentation: analysis by immunogold electron microscopy combined with i n situ nick end-labeling. Circulation 98, 1422–1430 (1998).

    Article  CAS  Google Scholar 

  63. Muzio, M. et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817–827 (1996).

    Article  CAS  Google Scholar 

  64. Kuwana, T. et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111, 331–342 (2002).

    Article  CAS  Google Scholar 

  65. Guo, B. et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423, 456–461 (2003).

    Article  ADS  CAS  Google Scholar 

  66. Schuler, M., Bossy-Wetzel, E., Goldstein, J. C., Fitzgerald, P. & Green, D. R. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J. Biol. Chem. 275, 7337–7342 (2000).

    Article  CAS  Google Scholar 

  67. Lin, B. et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116, 527–540 (2004).

    Article  CAS  Google Scholar 

  68. Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388, 300–304 (1997).

    Article  ADS  CAS  Google Scholar 

  69. Holley, C. L., Olson, M. R., Colon-Ramos, D. A. & Kornbluth, S. Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition. Nature Cell Biol. 4, 439–444 (2002).

    Article  CAS  Google Scholar 

  70. Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000).

    Article  CAS  Google Scholar 

  71. Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000).

    Article  CAS  Google Scholar 

  72. Martins, L. M. et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J. Biol. Chem. 277, 439–444 (2002).

    Article  CAS  Google Scholar 

  73. Bossy-Wetzel, E., Barsoum, M. J., Godzik, A., Schwarzenbacher, R. & Lipton, S. A. Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr. Opin. Cell Biol. 15, 706–716 (2003).

    Article  CAS  Google Scholar 

  74. Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L. & Youle, R. J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell. 15, 5001–5011 (2004).

    Article  CAS  Google Scholar 

  75. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).

    Article  CAS  Google Scholar 

  76. Cipolat, S. et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126, 163–175 (2006).

    Article  CAS  Google Scholar 

  77. Ng, F. W. et al. p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum. J. Cell Biol. 139, 327–338 (1997).

    Article  CAS  Google Scholar 

  78. Breckenridge, D. G., Stojanovic, M., Marcellus, R. C. & Shore, G. C. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J. Cell Biol. 160, 1115–1127 (2003).

    Article  CAS  Google Scholar 

  79. Roth, W. et al. Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways. Cell Death Differ. 10, 1178–1187 (2003).

    Article  CAS  Google Scholar 

  80. Mahul-Mellier, A. L., Hemming, F. J., Blot, B., Fraboulet, S. & Sadoul, R. Alix, making a link between apoptosis-linked gene-2, the endosomal sorting complexes required for transport, and neuronal death in vivo. J. Neurosci. 26, 542–549 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We apologize to all colleagues whose papers we were unable to cite owing to space limitations. We thank S. Rabizadeh, A. Kurakin, V. Galvan, D. Madden, L. Egger, J. Fombonne, T.-V. Nguyen, N. Rooke, K. Niazi, A. Swistowski, K. Poksay and S. Chen for critical reading of the manuscript, and M. Susag, L. Sheridan and R. Abulencia for manuscript preparation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dale E. Bredesen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bredesen, D., Rao, R. & Mehlen, P. Cell death in the nervous system. Nature 443, 796–802 (2006). https://doi.org/10.1038/nature05293

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05293

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing