Abstract
Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified as the product of a gene upregulated in prostate tumor cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase Cζ, Bcl-2, and caspase-8. A rapid increase in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction. The mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-κB and suppression of Bcl-2 expression and/or function. Studies of postmortem tissues from patients and animal models of neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis, have documented increased levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration. A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.
Similar content being viewed by others
References
Aguirre T., Van Den Bosch L., Goetschalckx K., Tilkin P., Mathijs G., Cassiman J. J., et al. (1998) Increased sensitivity of fibroblasts from amyotrophic lateral sclerosis patients to oxidative stress. Ann. Neurol. 43, 452–457.
Alexi T., Hughes P. E., Knusel B., and Tobin A. J. (1998) Metabolic compromise with systemic 3-nitropropionic acid produces striatal apoptosis in Sprague-Dawley rats but not in BALB/c ByJ mice. Exp. Neurol. 153, 74–93.
Ankarcrona M., Dypubkt J. M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton S. A., et al. (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15, 961–973.
Anrather J., Csizmadia V., Soares M. P., and Winkler H. (1999) Regulation of NF-κB RelA phosphorylation and transcriptional activity by p21(ras) and protein kinase Cζ in primary endothelial cells. J. Biol. Chem. 274, 13,594–13,603.
Armstrong J. F., Pritchard-Jones K., Bickmore W. A., Hastie N. D., and Bard J. B. (1993) The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo. Mech. Dev. 40, 85–97.
Bandmann O., Marsden C. D., and Wood N. W. (1998) Genetic aspects of Parkinson’s disease. Mov. Disord. 13, 203–211.
Barger S. W., Horster D., Furukawa K., Goodman Y., Krieglstein J., and Mattson M. P. (1995) Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc. Natl. Acad. Sci. USA 92, 9328–9332.
Beal, M. F. (1994) Neurochemistry and toxin models in Huntington’s disease. Curr. Opinion Neurol. 7, 542–547.
Beal M. F., Ferrante R. J., Browne S. E., Matthews R. T., Kowall N. W., and Brown R. H. (1997) Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42, 644–654.
Berra E., Municio M. M., Sans L., Frutos S., Diaz-Meco M. T., and Moscat J. (1997) Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade. Mol. Cell. Biol. 17, 4346–4354.
Boghaert E. R., Sells S. F., Walid A. J., Malone A. P., Williams N. M., Winstein M. H., et al. (1997) Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues. Cell Growth Differ. 8, 881–890.
Bruce-Keller A. J., Begley J. G., Fu W., Butterfield D. A., Bredesen D. E., Hutchins J. B., et al. (1997) Bcl-2 protects isolated plasma and mitochondrial membranes against lipid peroxidation induced by hydrogen peroxide and amyloid β-peptide. J. Neurochem. 70, 31–39.
Bruijn L. I., Beal M. F., Becher M. W., Schulz J. B., Wong P. C., Price D. L., et al. (1997) Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. Proc. Natl. Acad. Sci. USA 94, 7606–7611.
Chan S. L. and Mattson M. P. (1999) Caspase and calpain substrates: roles in synaptic plasticity and cell death. J. Neurosci. Res. 58, 167–190.
Chan S. L., Tammariello S. P., Estus S., and Mattson M. P. (1999) Par-4 mediates trophic factor withdrawal-induced apoptosis of hippocampal neurons: actions prior to mitochondrial dysfunction and caspase activation. J. Neurochem. 73, 502–512.
Chou S. M., Wang H. S., Taniguchi A., and Bucala R. (1998) Advanced glycation endproducts in neurofilament conglomeration of motoneurons in familial and sporadic amyotrophic lateral sclerosis. Mol. Med. 4, 324–332.
Cudkowicz M. E., McKenna-Yasek D., Sapp P. E., Chin W., Geller B. Hayden D. L., et al. (1997) Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41, 210–221.
Deveraux Q. L. and Reed J. C. (1999) Inhibitor of apoptosis proteins (IAPs), in Programmed Cell Death, vol. 1. (Mattson M. P., Rangnekar V., and Estus S., eds.), JAI, Greenwich, CT, in press.
Deveraux Q. L., Roy N., Stennicke H. R., Van Arsdale T., Zhou Q., Srinivasula S. M., et al. (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223.
Diaz-Meco M. T., Municio M. M., Frutos S., Sanchez P., Lozano J., Sanz L., et al. (1996) The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 86, 777–786.
Duan W., Rangnekar V., and Mattson M. P. (1999a) Par-4 production in synaptic compartments following apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration. J. Neurochem. 72, 2312–2322.
Duan W., Zhang Z., Gash D. M., and Mattson M. P. (1999b) Participation of Par-4 in degeneration of dopaminergic neurons in models of Parkinson’s disease. Ann. Neurol. in press.
Frutos S., Moscat J., and Diaz-Meco M. T. (1999) Cleavage of zetaPKC but not lambda/iotaPKC by caspase-3 during UV-induced apoptosis. J. Biol. Chem. 274, 10,765–10,770.
Greenlund L. J., Deckwerth T. L., and Johnson E. M. (1995) Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 14, 303–315.
Guo Q., Furukawa K., Sopher B. L., Pham D. G., Robinson N., Martin G. M., et al. (1996) Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. NeuroReport 8, 379–383.
Guo Q., Sopher B. L., Pham D. G., Furukawa K., Robinson N., Martin G. M., et al. (1997) 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.
Guo Q., Fu W., Xie J., Luo H., Sells S. F., Geddes J. W., et al. (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer’s disease. Nature Med. 4, 957–962.
Guo Q., Chan S. L., and Kruman I. (1999a) The Bcl-2 family of proteins and their actions within the molecular machinery of cell death, in Programmed Cell Death, vol. 1. (Mattson M. P., Rangnekar V., and Estus, S., eds), JAI, Greenwich, CT, in press.
Guo Q., Fu W., Sopher B. L., Miller M. W., Ware C. B., Martin, G. M., et al. (1999b) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knockin mice. Nature Med. 5, 101–107.
Gurney M. E., Pu H., Chiu A. Y., Dal Canto M. C., Polchow C. Y., Alexander D. D., et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775.
Jenner P. and Olanow C. W. (1998) Understanding cell death in Parkinson’s disease. Ann. Neurol. 44, S72–84.
Johnstone R. W., See R. H., Sells S. F., Wang J., Muthukkumar S., Englert C., et al. (1996) A novel repressor, Par-4, modulates transcription and growth suppression functions of the Wilms tumor suppressor WT1. Mol. Cell. Biol. 16, 6945–6956.
Johnstone R. W., Tommerup N., Hansen C., Vissing H., and Shi Y. (1998) Mapping of the human PAWR (par-4) gene to chromosome 12q21. Genomics 53, 241–243.
Keller J. N., Pang Z., Geddes J. W., Begley J. G., Germeyer A., Waeg G., et al. (1997) Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid-β peptide: Role of the lipid peroxidation product 4-hydroxynonenal. J. Neurochem. 69, 273–284.
Keller J. N., Kindy M. S., Holtsberg F. W., St Clair D. K., Yen H. C., Germeyer A., Steiner S. M., et al. (1998) Mitochondrial MnSOD prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation and mitochondrial dysfunction. J. Neurosci. 18, 687–697.
Kruman I., Bruce-Keller A. J., Bredesen D. E., Waeg G., and Mattson M. P. (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci. 17, 5089–5100.
Kruman I., Guo Q., and Mattson M. P. (1998) Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J. Neurosci. Res. 51, 293–308.
Kruman I., Pang Z., Geddes J. W., and Mattson M. P. (1999a) Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J. Neurochem. 72, 529–540.
Kruman I., Nath A., Maragos W. F., Chan S. L., Jones M., Rangnekar V. M., et al. (1999b) Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Am. J. Pathol. 155, 39–46.
Langston J. W. (1998) Epidemiology versus genetics in Parkinson’s disease: progress in resolving an age-old debate. Ann. Neurol. 44, S45-S52.
Mark R. J., Hensley K., Butterfield D. A., and Mattson M. P. (1995) Amyloid β-peptide impairs ionmotive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J. Neurosci. 15, 6239–6249.
Mark R. J., Lovell M. A., Markesbery W. R., Uchida K., and Mattson M. P. (1997a) A role for 4- hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β-peptide. J. Neurochem. 68, 255–264.
Mark R. J., Pang Z., Geddes J. W., Uchida K., and Mattson M. P. (1997b) Amyloid β-peptide impairs glucose uptake in hippocampal and cortical neurons: Involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046–1054.
Mattson M. P. (1997) Cellular actions of β-amyloid precursor protein, and its soluble and fibrillogenic peptide derivatives. Physiol. Rev. 77, 1081–1132.
Mattson M. P. and Duan W. (1999) Biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders. J. Neurosci. Res. 58, 152–166.
Mattson M. P. and Goodman Y. (1995) Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium. Brain Res. 676, 219–224.
Mattson M. P., Cheng B., Davis D., Bryant K., Lieberburg I., and Rydel R. E. (1992) β-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389.
Mattson M. P., Tomaselli K., and Rydel R. E. (1993) Calcium-destabilizing and neurodegenerative effects of aggregated b-amyloid peptide are attenuated by basic FGF. Brain Res. 621, 35–49.
Mattson M. P., Keller J. N., and Begley J. G. (1998) Evidence for synaptic apoptosis. Exp. Neurol. 153, 35–48.
Mattson M. P., Culmsee C., Yu Z., and Camandola S. (1999) Roles of NF-κB in neuronal survival and plasticity. J. Neurochem. in press.
Menke A. L., van der Eb A. J., and Jochemsen A. G. (1998) The Wilms’ tumor 1 gene: oncogene or tumor suppressor gene? Int. Rev. Cytol. 181, 151–212.
Mochizuki H., Goto K., Mori H., and Mizuno Y. (1996) Histochemical detection of apoptosis in Parkinson’s disease. J. Neurol. Sci. 137, 120–123.
Moratalla R., Quinn B., DeLanney L. E., Irwin I., Langston J. W., and Graybiel A. M. (1992) Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc. Natl. Acad. Sci. USA 89, 3859–3863.
Mu X., He J., Anderson D. W., Trojanowski J. Q., and Springer J. E. (1996) Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. Ann. Neurol. 40, 379–386.
Oppenheim R. W. (1991) Cell death during development of the nervous system. Annu. Rev. Neurosci. 14, 453–501.
Pedersen W. A., Luo H., Kruman I., Kasarskis E., and Mattson M. P. (1999) Involvement of the prostate apoptosis response-4 (Par-4) protein in motor neuron degeneration in ALS. Soc. Neurosci. Abst. 25, 49.
Petersen A., Mani K., and Brundin P. (1999) Recent advances on the pathogenesis of Huntington’s disease. Exp. Neurol. 157, 1–18.
Portera-Cailliau C., Hedreen J. C., Price D. L., and Koliatsos V. E. (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J. Neurosci. 15, 3775–3787.
Puls A., Schmidt S. S., Grawe F., and Stabel S. (1997) Interaction of protein kinase C zeta with ZIP, a novel protein kinase C-binding protein. Proc. Natl. Acad. Sci. USA 94, 6191–6196.
Qiu G., Ahmed M., Sells S. F., Mohiuddin M., Weinstein M. H., and Rangnekar V. M. (1999) Oncogene Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4. 18, 623–631.
Rabizadeh S., Gralla E. B., Borchelt D. R., Gwinn R., Valentine J. S., Sisodia S., et al. (1995) Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: Studies in yeast and neural cells. Proc. Natl. Acad. Sci. USA 92, 3024–3028.
Sanchez I., Xu C. J., Juo P., Kakizaka A., Blenis J., and Yuan, J. (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22, 623–633.
Saudou F., Finkbeiner S., Devys D., and Greenberg M. E. (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66.
Schapira A. H., Gu M., Taanman J. W., Tabrizi S. J., Seaton T., Cleeter M., et al. (1998) Mitochondria in the etiology and pathogenesis of Parkinson’s disease. Ann. Neurol. 44, S89–98.
Sells S. F., Wood D. P., Joshi-Barve S. S., Muthukkumar S., Jacob R. J., Crist S. A., et al. (1994) Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ. 5, 457–466.
Sells S. F., Han S. S., Muthukkumar S., Maddiwar N., Johnstone R., Boghaert E., et al. (1997) Expression and function of the leucine zipper protein Par-4 in apoptosis. Mol. Cell. Biol. 17, 3823–3832.
Shih S. C., Mullen A., Abrams K., Mukhopadhyay D., and Claffey K. P. (1999) Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells. J. Biol. Chem. 274, 15,407–15,414.
Steller, H. (1995) Mechanisms and genes of cellular suicide. Science 267, 1445–1449.
Taglialatela G., Robinson R., and Perez-Polo J. R. (1997) Inhibition of nuclear factor κB (NFκB) activity induces nerve growth factor-resistant apoptosis in PC12 cells. J. Neurosci. Res. 47, 155–162.
Tamatani M., Che Y. H., Matsuzaki H., Ogawa S., Okado H., Miyake S., et al. (1999) Tumor necrosis factor induces bcl-2 and bcl-x expression through NFκB activation in primary hippocampal neurons. J. Biol. Chem. 274, 8531–8538.
Wiedau-Pazos M., Goto J. J., Rabizadeh S., Gralla E. B., Roe J. A., Lee M. K., et al. (1996) Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 271, 515–518.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mattson, M.P., Duan, W., Chan, S.L. et al. Par-4. J Mol Neurosci 13, 17–30 (1999). https://doi.org/10.1385/JMN:13:1-2:17
Issue Date:
DOI: https://doi.org/10.1385/JMN:13:1-2:17