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Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

Nature Medicine volume 4, pages 957–962 (1998)Cite this article

Abstract

Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upreguiated in prostate cancer cells undergoing apoptosis1,2. Par-4 is expressed in the nervous system3, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid β-protein (Aβ) may play a role in this4–11. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawl. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.

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References

  1. Sells, S.F. et al. Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ. 5, 457–466 (1994).

    CAS  PubMed  Google Scholar 

  2. Sells, S.F. et al. Expression and function of the leucine zipper protein Par-4 in apoptosis. Mol. Cell. Biol. 17, 3823–3832 (1997).

    Article  CAS  Google Scholar 

  3. Boghaeit, E.R. et al. Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues. Cell Growth Differ. 8, 881–890 (1997).

    Google Scholar 

  4. Mattson, M.P. Cellular actions of β-amyloid precursor protein, and its soluble and fibrillogenic peptide derivatives. Physiol. Rev. 77, 1081–1132 (1997).

    Article  CAS  Google Scholar 

  5. Benzi, G. & Moretti, A. Contribution of mitochondrial alterations to brain aging. Adv. Cell Aging Gerontol. 2, 129–160 (1997).

    Article  CAS  Google Scholar 

  6. Mattson, M.P. & Lindvall, O. Neurotrophic factor and cytokine signaling in the aging brain. Adv. Cell Aging Gerontol. 2, 299–345 (1997).

    Article  CAS  Google Scholar 

  7. Su, J.H. et al. Immunocytochemical evidence for apoptosis in Alzheimer's disease. Neuroreport 5, 2529–2533 (1994).

    Article  CAS  Google Scholar 

  8. Smale, G., Nichols, N.R. & Brady, D.R. Evidence for apoptotic cell death in Alzheimer's disease. Exp. Neural. 133, 225–230 (1995).

    Article  CAS  Google Scholar 

  9. Loo, D.T. et al. Apoptosis is induced by β amyloid in cultured central nervous system neurons. Proc. Natl. Acad. Sci. USA 90, 7951–7955 (1993).

    Article  CAS  Google Scholar 

  10. Kruman, I. et al. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci. 17, 5089–5100 (1997).

    Article  CAS  Google Scholar 

  11. Steller, H. Mechanisms and genes of cellular suicide. Science 267, 1445–1449 (1995).

    Article  CAS  Google Scholar 

  12. Kruman, I. et al. Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J. Neurosci. Res. 51, 293–308 (1998).

    Article  CAS  Google Scholar 

  13. Diaz-Meco, M.T. et al. The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 86, 777–786 (1996).

    Article  CAS  Google Scholar 

  14. Cohen, C.M. Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16 (1997).

    Article  CAS  Google Scholar 

  15. Keller, J.N. et al. Mitochondrial MnSOD prevents neural apoptosis and reduces ischemic brain injury: suppression of oxyradical production, lipid peroxidation and mitochondrial dysfunction. J. Neurosci. 18, 687–697 (1998).

    Article  CAS  Google Scholar 

  16. St George-Hyslop, P. et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nature Gen. 2, 330–334 (1992).

    Article  CAS  Google Scholar 

  17. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995).

    Article  CAS  Google Scholar 

  18. Guo, Q. et al. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17, 4212–4222 (1997).

    Article  CAS  Google Scholar 

  19. Janicki, S. & Monteiro, M.J. Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I). J. Cell Biol. 139, 485–495 (1997).

    Article  CAS  Google Scholar 

  20. Guo, Q., Christakos, S., Robinson, N. & Mattson, M.P. Calbindin blocks the proapoptotic actions of mutant presenilin-1: reduced oxidative stress and preserved mitochondrial function. Proc. Natl. Acad. Sci. USA 95, 3227–3232 (1998).

    Article  CAS  Google Scholar 

  21. Johnstone, R.W. et al. A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. Mol. Cell. Biol. 16, 6945–6956 (1996).

    Article  CAS  Google Scholar 

  22. Lucas, M. & Sanchez-Margalet, V. Protein kinase C involvement in apoptosis. Gen. Pharmacol. 26, 881–887 (1995).

    Article  CAS  Google Scholar 

  23. Goedert, M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 16, 460–465 (1993).

    Article  CAS  Google Scholar 

  24. Hardy, J. Amyloid, the presenilins and Alzheimer's disease. TINS 20, 154–159 (1997).

    CAS  PubMed  Google Scholar 

  25. Mark, R.J., Blanc, E.M. & Mattson, M.P. Amyloid beta-peptide and oxidative cellular injury inAlzheimer's disease. Mol. Neurobiol. 12, 211–224 (1996).

    Article  CAS  Google Scholar 

  26. Keller, J.N. et al. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J. Neurosci. 18, 4439–4450 (1998).

    Article  CAS  Google Scholar 

  27. Mattson, M.P., Robinson, N. & Guo, Q. Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1. Neuroreport 8, 3817–3821 (1997).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Sanders-Brown Research Center on Aging, University of Kentucky, Lexington, KY, 40536

    Qing Guo, Weiming Fu, Jun Xie, Hong Luo, J.W. Geddes, Vimala Bondada & Mark P. Mattson

  2. Department of Surgery and Microbiology and Immunology and Markey Cancer Centre, University of Kentucky, Lexington, KY, 40536

    Stephen F. Sells & Vivek M. Rangnekar

  3. Department of Anatomy & Neurobiology, University of Kentucky, Lexington, KY, 40536

    J.W. Geddes & Mark P. Mattson

Authors
  1. Qing Guo
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  2. Weiming Fu
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  3. Jun Xie
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  4. Hong Luo
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  5. Stephen F. Sells
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  6. J.W. Geddes
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  7. Vimala Bondada
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  8. Vivek M. Rangnekar
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  9. Mark P. Mattson
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Correspondence to Mark P. Mattson.

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Guo, Q., Fu, W., Xie, J. et al. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med 4, 957–962 (1998). https://doi.org/10.1038/nm0898-957

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