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Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;7(1):21–34. doi: 10.1111/j.1582-4934.2003.tb00199.x

Physiological and pathological roles of Apaf1 and the apoptosome

E Ferraro 1, M Corvaro 1, F Cecconi 1,
PMCID: PMC6740308  PMID: 12767258

Abstract

Different cellular pathways can lead to apoptosis. Apaf1 is the molecular core of the apoptosome, a multiproteic complex mediating the so‐called mitochondrial pathway of cell death. The importance of this pathway during development has been clearly demonstrated by knocking out key genes. Also, the relevance of Apaf1 dosage during development has been recently underlined. Moreover, a growing body of evidences seems to point out a possible role of the mitochondria‐dependent apoptosis in different pathologies. In particular, we discuss here some recent evidences regarding the putative role of the apoptosome in neurodegeneration and cancer.

Keywords: apoptosis, cell death, neurodegeneration, Apaf1, apoptosome, caspases

References

  • 1. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Jacobson M.D., Weil M., Raff M.C., Programmed cell death in animal development, Cell, 88: 347–354, 1997. [DOI] [PubMed] [Google Scholar]
  • 3. Earnshaw W.C., Martins L.M., Kaufmann S.H., Mammalian caspases: structure, activation, substrates, and functions during apoptosis, Annu. Rev. Biochem., 68: 383–424, 1999. [DOI] [PubMed] [Google Scholar]
  • 4. Martinou J.C., Green D.R., Breaking the mitochondrial barrier, Nat. Rev. Mol. Cell Biol., 2: 63–67, 2001. [DOI] [PubMed] [Google Scholar]
  • 5. Zamzami N., Kroemer G., The mitochondrion in apoptosis: how Pandora's box opens, Nat. Rev. Mol. Cell. Biol., 2: 67–71, 2001. [DOI] [PubMed] [Google Scholar]
  • 6. Li P., Nijhawan D., Budihardjo I., Srinivasula S.M., Ahmad M., Alnemri E.S., Wang X., Cytochrome c and dATP‐dependent formation of Apaf‐1/caspase‐9 complex initiates an apoptotic protease cascade, Cell, 91: 479–489, 1997. [DOI] [PubMed] [Google Scholar]
  • 7. Acehan D., Jiang X., Morgan D.G., Heuser J.E., Wang X., Akey C.W., Three‐dimensional structure of the apoptosome. Implications for assembly, procaspase‐9 binding, and activation, Mol. Cell, 9: 423–432, 2002. [DOI] [PubMed] [Google Scholar]
  • 8. Riedl S.J., Renatus M., Schwarzenbacher R., Zhou Q., Sun C., Fesik S.W., Liddington R.C., Salvesen G.S., Structural basis for the inhibition of caspase‐3 by XIAP, Cell, 104: 791–800, 2001. [DOI] [PubMed] [Google Scholar]
  • 9. Bratton S.B., Walker G., Srinivasula S.M., Sun X.M., Butterworth M., Alnemri E.S., Cohen G.M., Recruitment, activation and retention of caspases −9 and −3 by Apaf‐1 apoptosome and associated XIAP complexes, EMBO J., 20: 998–1009, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Verhagen A.M., Ekert P.G., Pakusch M., Silke J., Connolly L.M., Reid G.E., Moritz R.L., Simpson R.J., Vaux D.L., Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins, Cell, 102: 43–53, 2000. [DOI] [PubMed] [Google Scholar]
  • 11. Verhagen A.M., Silke J., Ekert P.G., Pakusch M., Kaufmann H., Connolly L.M., Day C.L., Tikoo A., Burke R., Wrobel C., Moritz R.L., Simpson R.J., Vaux D.L., HtrA2 promotes cell death through its serine protease acti vity and its ability to antagonize inhibitor of apoptosis proteins, J. Biol. Chem., 277: 445–454, 2002. [DOI] [PubMed] [Google Scholar]
  • 12. Saleh A., Srinivasula S.M., Balkir L., Robbins P.D., Alnemri E.S., Negative regulation of the Apaf‐1 apoptosome by Hsp70, Nat. Cell. Biol., 2: 476–483, 2000. [DOI] [PubMed] [Google Scholar]
  • 13. Pandey P., Saleh A., Nakazawa A., Kumar S., Srinivasula S.M., Kumar V., Weichselbaum R., Nalin C., Alnemri E.S., Kufe D., Kharbanda S., Negative regulation of cytochrome c‐mediated oligomerization of Apaf‐1 and activation of procaspase‐9 by heat shock protein 90, EMBO J., 19: 4310–4322, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Bruey J.M., Ducasse C., Bonniaud P., Ravagnan L., Susin S.A., Diaz‐Latoud C., Gurbuxani S., Arrigo A.P., Kroemer G., Solary E., Garrido C., Hsp27 negatively regulates cell death by interacting with cytochrome c, Nat. Cell. Biol., 2: 645–652, 2000. [DOI] [PubMed] [Google Scholar]
  • 15. Cecconi F., Apaf1 and the apoptotic machinery, Cell Death Differ., 6: 1087–1098, 1999. [DOI] [PubMed] [Google Scholar]
  • 16. Cecconi F., Alvarez‐Bolado G., Meyer B.I., Roth K.A., Gruss P., Apaf1 (CED‐4 homolog) regulates programmed cell death in mammalian development, Cell., 94(6): 727–37, 1998. [DOI] [PubMed] [Google Scholar]
  • 17. Sperandio S., de Belle I., Bredesen D.E., An alternative, nonapoptotic form of programmed cell death, Proc. Natl. Acad. Sci. USA, 97: 14376–81, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Susin S.A., Lorenzo H.K., Zamzami N., Marzo I., Snow B.E., Brothers G.M., Mangion J., Jacotot E., Costantini P., Loeffler M., Larochette N., Goodlett D.R., Aebersold R., Siderovski D.P., Penninger J.M., Kroemer G., Molecular characterization of mitochondrial apoptosis‐inducing factor., Nature, 397: 441–6, 1999. [DOI] [PubMed] [Google Scholar]
  • 19. Honarpour N., Gilbert S.L., Lahn B.T., Wang X., Herz J., Apaf‐1 deficiency and neural tube closure defects are found in fog mice, Proc. Natl. Acad. Sci. USA, 98: 9683–9687, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Moreno S., Ferraro E., Eckert S., Cecconi F., Apaf1 reduced expression levels generate a mutant phenotype in adult brain and skeleton, Cell Death Differ., 9: 340–342, 2002. [DOI] [PubMed] [Google Scholar]
  • 21. Vousden K.H., p53: death star, Cell, 103: 691–694, 2000. [DOI] [PubMed] [Google Scholar]
  • 22. Macleod K., Tumor suppressor genes, Curr. Op. in Genet. Dev., 10: 81–93, 2000. [DOI] [PubMed] [Google Scholar]
  • 23. Soengas M.S., Alarcon R.M., Yoshida H., Giaccia A.J., Hakem R., Mak T.W., Lowe S.W., Apaf‐1 and Caspase‐9 in p53‐dependent apoptosis and tumor inhibition, Science, 284: 156–159, 1999. [DOI] [PubMed] [Google Scholar]
  • 24. Guo Z., Yikang S., Yoshida H., Mak T.W., Zacksenhaus E., Inactivation of retinoblastoma tumor suppressor induces apoptosis protease‐activating factor‐1 dependent and independent apoptotic pathways during embryogenesis, Cancer Res., 61: 8395–8400, 2001. [PubMed] [Google Scholar]
  • 25. Kimura M., Kurukawa T., Abe T., Yatsuoka T., Youssef E.M., Yokoyama T. et al., Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer, Cancer Res., 58: 2456–2460, 1998. [PubMed] [Google Scholar]
  • 26. Bala S., Oliver H., Renault B., Montgomery K., Dutta S., Rao P., Houldsworth J., Kucherlapati R., Wang X., Chaganti R.S.K., Murty V.V.V.S., Genetic analysis of the APAF1 Gene in male germ cells tumors, Genes Chromosomes Cancer, 28: 258–268, 2000. [DOI] [PubMed] [Google Scholar]
  • 27. Yamamoto H., Gil J., Schwartz S. jr, Perucho M., Frameshift mutations in Fas, Apaf‐1, and Bcl‐10 in gastrointestinal cancer of the microsatellite mutator phenotype, Cell Death Differ., 7: 238–239, 2000. [DOI] [PubMed] [Google Scholar]
  • 28. Soengas M.S., Capodieci P., Polsky D., Mora J., Esteller M., Opitz‐araya X., McCombie R., Herman J.G., Gerald W.L., Lazebnik Y.A., Cordòn‐cardò C., Lowe S.W., Inactivation of the apoptosis effector Apaf‐1 in malignant melanoma, Nature, 409: 207–211, 2001. [DOI] [PubMed] [Google Scholar]
  • 29. Wolf B.B., Schuler M., Li W., Eggers‐Sedlet B., Lee W., Tailor P., Fitzgerald P., Mills G.B., Green D.R., Defective cytochrome c‐dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor‐1 activity, J Biol Chem., 276: 34244–34251, 2001. [DOI] [PubMed] [Google Scholar]
  • 30. Liu J.R., Opipari A.W., Tan L., Jiang Y., Zhang Y., Tang H., Nunez G., Dysfunctional apoptosome activation in ovarian cancer: implications for chemoresistance, Cancer Res., 62: 924–931, 2002. [PubMed] [Google Scholar]
  • 31. Gilberston R., Paediatric embryonic brain tumors: biological and clinical relevance of molecoular genetics abnormalities, Eur J. Cancer, 38: 675–685, 2002. [DOI] [PubMed] [Google Scholar]
  • 32. Pomeroy S.L., Tamayo P., Gaasenbeek M., Sturla L.M., Angelo M., McLaughlin M.E., Kim J.Y.H., Goumnerova L.C., Black P.M. et al., Prediction of central nervous system embryonal tumour outcome based on gene expression, Nature, 415: 436–442, 2002. [DOI] [PubMed] [Google Scholar]
  • 33. Teitz T., Wei T., Liu D., Valentine V., Valentine M., Grenet J., Lahti J.M., Kidd V. J., Caspase‐9 and Apaf‐1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplyfied MYCN, Oncogene, 21: 1848–1858, 2002. [DOI] [PubMed] [Google Scholar]
  • 34. Fortin A., Cregan S.P., MacLaurin J.G., Kushwaha N., Hickman E.S., Thompson C.S., Hakim A., Albert P.R., Cecconi F., Helin K., Park D.S., Slack R.S., APAF1 is a key trascriptional target for p53 in the regulation of the neuronal cell death., J. Cell Biol., 155: 207–16, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Moroni M.C., Hickman E.S., Lazzarini Denchi E., Caprara G., Colli E., Cecconi F., Muller H., Helin K., Apaf‐1 is a trascriptional target for e2f and p53, Nature Cell Biol., 3: 552–558, 2001. [DOI] [PubMed] [Google Scholar]
  • 36. Kannan K., Kaminski N., Rechavi G., Jacob‐Hirsch J., Amariglio N., Givol D., DNA microarray analysis of genes involved in p53 mediated apoptosis: activation of Apaf‐1, Oncogene, 20: 3449–3455, 2001. [DOI] [PubMed] [Google Scholar]
  • 37. Rozenfeld‐granot G., Krishnamurthy J., Kannan K., Toren A., Amariglio N., Givol D., Rechavi G., A positive feedback mechanism in the transcriptional activation of Apaf‐1 by p53 and the coactivator Zac‐1, Oncogene, 21: 1469–1467, 2002. [DOI] [PubMed] [Google Scholar]
  • 38. Coldwell M.J., Mitchell S.A., Stoneley M., MacFarlane M., Willis A.E., Initiation of Apaf‐1 translation by internal ribosome entry, Oncogene, 19: 899–905, 2000. [DOI] [PubMed] [Google Scholar]
  • 39. Mitchell S.A., Brown E.C., Coldwell M.J., Jackson R.J., Willis A.E., Protein factor requirements of the Apaf1 internal ribosome entry segment: roles of polypyrimidine tract binding protein and upstream of N‐ras, Mol. Cell Biol., 21: 3364–3374, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Chauhan D., Hideshima T., Rosen S., Reed J.C., Kharbanda S., Anderson K.C., Apaf‐1/cytochrome c‐independent and Smac‐dependent induction of apoptosis in multiple myeloma (MM) cells, J. Biol. Chem., 276: 24453–24456, 2001. [DOI] [PubMed] [Google Scholar]
  • 41. Shinoura N., Sakurai S., Asai A., Kirino T., Hamada H., Over‐expression of APAF‐1 and caspase‐9 augments radiation‐induced apoptosis in U‐373MG glioma cells, Int. J. Cancer., 93: 252–261, 2001. [DOI] [PubMed] [Google Scholar]
  • 42. Mizutani Y., Sato N., Kawauchi A., Nonomura N., Fukushima M., Miki T., Cisplatin‐induced in vivo differentiation of human embryonal carcinoma, BJU international, 89: 454–458, 2002. [DOI] [PubMed] [Google Scholar]
  • 43. Jones P.A., Death and methilation, Nature, 409: 141–144, 2001. [DOI] [PubMed] [Google Scholar]
  • 44. Troy C.M., Salvesen G.S., Caspases on the brain, J. Neurosci. Res., 69: 145–50, 2002. [DOI] [PubMed] [Google Scholar]
  • 45. Weidemann A., Paliga K., Durrwang U., Reinhard F.B., Schuckert O., Evin G., Masters C.L., Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase‐like proteases, J. Biol. Chem., 274: 5823–5829, 1999. [DOI] [PubMed] [Google Scholar]
  • 46. Wellington C.L., Ellerby L.M., Hackam A.S., Margolis R.L., Trifiro M.A., Singaraja R., McCutcheon K., Salvesen G.S., Propp .SS., Bromm M., Rowland K.J., Zhang T., Rasper D., Roy S., Thornberry N., Pinsky L., Kakizuka A., Ross C.A., Nicholson D.W., Bredesen D.E., Hayden M.R., Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract, J. Biol. Chem., 273: 9158–9167, 1998. [DOI] [PubMed] [Google Scholar]
  • 47. Gervais F.G., Xu D., Robertson G.S., Vaillancourt J.P., Zhu Y., Huang J., LeBlanc A., Smith D., Rigby M., Shearman M.S., Clarke E.E., Zheng H., Van Der Ploeg L.H., Ruffolo S.C., Thornberry N.A., Xanthoudakis S., Zamboni R.J., Roy S., Nicholson D.W., Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid‐beta precursor protein and amyloidogenic A beta peptide formation, Cell, 97: 395–406, 1999. [DOI] [PubMed] [Google Scholar]
  • 48. Pellegrini L., Passer B.J., Tabaton M., Ganjei J.K., D'Adamio L., Alternative, non‐secretase processing of Alzheimer's beta‐amyloid precursor protein during apoptosis by caspase −6 and −8, J. Biol. Chem., 274: 21011–6, 1999. [DOI] [PubMed] [Google Scholar]
  • 49. Tanzi M., Bellelli E., Benaglia G., Cavatorta E., Merialdi A., Mordacci E., Ribero M.L., Tagger A., Verrotti C., Volpicelli A., Alternative cleavage of Alzheimer‐associated presenilins during apoptosis by a caspase‐3 family protease, Science, 277: 373–376, 1997. [DOI] [PubMed] [Google Scholar]
  • 50. Lunkes A., Lindenberg K.S., Ben‐Haiem L., Weber C., Devys D., Landwehrmeyer G.B., Mandel J.L., Trottier Y., Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions, Mol. Cell., 10: 259–269, 2002. [DOI] [PubMed] [Google Scholar]
  • 51. Marx J., Neuroscience. New leads on the ‘how’ of Alzheimer's, Science, 293: 2192–2194, 2001. [DOI] [PubMed] [Google Scholar]
  • 52. Rohn T.T., Head E., Su J.H., Anderson A.J., Bahr B.A., Cotman C.W., Cribbs D.H., Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease, Am. J. Pathol., 158: 189–198, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. LeBlanc A., Liu H., Goodyer C., Bergeron C., Hammond J., Caspase‐6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease, J. Biol. Chem., 274: 23426–36, 1999. [DOI] [PubMed] [Google Scholar]
  • 54. Stadelmann C., Deckwerth T.L., Srinivasan A., Bancher C., Bruck W., Jellinger K., Lassmann H., Activation of caspase‐3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death., Am. J. Pathol., 155: 1459–66, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Lu D.C., Rabizadeh S., Chandra S., Shayya R.F., Ellerby L.M., Ye X., Salvesen G.S., Koo E.H., Bredesen D.E., A second cytotoxic proteolytic peptide derived from amyloid beta‐protein precursor, Nat. Med., 6: 397–404, 2000. [DOI] [PubMed] [Google Scholar]
  • 56. Li M., Ona V.O., Guegan C., Chen M., Jackson‐Lewis V., Andrews L.J., Olszewski A.J., Stieg P.E., Lee J.P., Przedborski S. Friedlander R.M., Functional role of caspase‐1 and caspase‐3 in an ALS transgenic mouse model, Science, 288: 335–9, 2000. [DOI] [PubMed] [Google Scholar]
  • 57. Pasinelli P., Houseweart M.K., Brown R.H. Jr, Cleveland D.W., Caspase −1 and −3 are sequentially activated in motor neuron death in Cu, Zn superoxide dismutase‐mediated familial amyotrophic lateral sclerosis, Proc. Natl. Acad. Sci. USA, 97: 13901–13906, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Sanchez I., Xu C.J., Juo P., Kakizaka A., Blenis J., Yuan J., Caspase‐8 is required for cell death induced by expanded polyglutamine repeats, Neuron, 22: 623–633, 1999. [DOI] [PubMed] [Google Scholar]
  • 59. Jeon B.S., Kholodilov N.G., Oo T.F., Kim S.Y., Tomaselli K.J., Srinivasan A., Stefanis L., Burke R.E., Activation of caspase‐3 in developmental models of programmed cell death in neurons of the substantia nigra, J. Neurochem., 73: 322–333, 1999. [DOI] [PubMed] [Google Scholar]
  • 60. Viswanath V., Wu Y., Boonplueang R., Chen S., Stevenson F.F., Yantiri F., Yang L., Beal M.F., Andersen J.K., Caspase‐9 activation results in downstream caspase‐8 activation and bid cleavage in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced Parkinson's disease, J. Neurosci., 21: 9519–28, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Love S., Barber R., Wilcock G.K., Neuronal death in brain infarcts in man, Neuropathol. Appl. Neurobiol., 26: 55–66, 2000. [DOI] [PubMed] [Google Scholar]
  • 62. Nicotera P., Apoptosis and age‐related disorders: role of caspase‐dependent and caspase‐independent pathways, Toxicol. Lett., 127: 189–195, 2002. [DOI] [PubMed] [Google Scholar]
  • 63. Forloni G., Bugiani O., Tagliavini F., Salmona M., Apoptosis‐mediated neurotoxicity induced by beta‐amyloid and PrP fragments, Mol. Chem. Neuropathol., 28: 163–171, 1996. [DOI] [PubMed] [Google Scholar]
  • 64. Ivins K.J., Thornton P.L., Rohn T.T., Cotman C.W., Neuronal apoptosis induced by beta‐amyloid is mediated by caspase‐8, Neurobiol. Dis., 6: 440–449, 1999. [DOI] [PubMed] [Google Scholar]
  • 65. Uetsuki T., Takemoto K., Nishimura I., Okamoto M., Niinobe M., Momoi T., Miura M., Yoshikawa K., Activation of neuronal caspase‐3 by intracellular accumulation of wild‐type Alzheimer amyloid precursor protein, J. Neurosci., 19: 6955–6964, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Kienlen‐Campard P., Miolet S., Tasiaux B., Octave J.N., Intracellular amyloid‐beta 1‐42, but not extracellular soluble amyloid‐beta peptides, induces neuronal apoptosis, J. Biol. Chem., 277: 15666–15670, 2002. [DOI] [PubMed] [Google Scholar]
  • 67. Zhang Y., McLaughlin R., Goodyer C., LeBlanc A., Selective cytotoxicity of intracellular amyloid beta peptide1‐42 through p53 and Bax in cultured primary human neurons., J. Cell Biol., 156: 519–529, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Wei W., Norton D.D., Wang X., Kusiak J.W., Abeta 17‐42 in Alzheimer's disease activates JNK and caspase‐8 leading to neuronal apoptosis, Brain, 125: 2036–2043, 2002. [DOI] [PubMed] [Google Scholar]
  • 69. Kim H.S., Lee J.H., Lee J.P., Kim E.M., Chang K.A., Park C.H., Jeong S.J., Wittendorp M.C., Seo J.H., Choi S.H., Suh Y.H., Amyloid beta peptide induces cytochrome c release from isolated mitochondria, Neuroreport, 13: 1989–1993, 2002. [DOI] [PubMed] [Google Scholar]
  • 70. Allen J.W., Eldadah B.A., Huang X., Knoblach S.M., Faden A.I., Multiple caspases are involved in beta‐amyloidinduced neuronal apoptosis, J. Neurosci. Res., 65: 45–53, 2001. [DOI] [PubMed] [Google Scholar]
  • 71. Nakagawa T., Zhu H., Morishima N., Li E., Xu J., Yankner B.A., Yuan J., Caspase‐12 mediates endoplasmicreticulum‐specific apoptosis and cytotoxicity by amyloidbeta, Nature, 403: 98–103, 2000. [DOI] [PubMed] [Google Scholar]
  • 72. Troy C.M., Rabacchi S.A., Friedman W.J., Frappier T.F., Brown K., Shelanski M.L., Caspase‐2 mediates neuronal cell death induced by beta‐amyloid, J. Neurosci., 20: 1386–1392, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Morishima Y., Gotoh Y., Zieg J., Barrett T., Takano H., Flavell R., Davis R.J., Shirasaki Y., Greenberg M.E., Betaamyloid induces neuronal apoptosis via a mechanism that involves the c‐Jun N‐terminal kinase pathway and the induction of Fas ligand, J. Neurosci., 21: 7551–7560, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. Wolozin B., Iwasaki K., Vito P., Ganjei J.K., Lacana E., Sunderland T., Zhao B., Kusiak J.W., Wasco W., D'Adamio L., Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation, Science, 274: 1710–1713, 1996. [DOI] [PubMed] [Google Scholar]
  • 75. Kim M., Lee H.S., LaForet G., McIntyre C., Martin E.J., Chang P., Kim T.W., Williams M., Reddy P.H., Tagle D., Boyce F.M., Won L., Heller A., Aronin N., DiFiglia M., Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition., J. Neurosci., 19: 964–973, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76. Miyashita T., Matsui J., Ohtsuka Y., Mami U., Fujishima S., Okamura‐Oho Y., Inoue T., Yamada M., Expression of extended polyglutamine sequentially activates initiator and effector caspases, Biochem. Biophys. Res. Commun., 257: 724–30, 1999. [DOI] [PubMed] [Google Scholar]
  • 77. Saudou F., Finkbeiner S., Devys D., Greenberg M.E., Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions, Cell, 95: 55–66, 1998. [DOI] [PubMed] [Google Scholar]
  • 78. Wellington C.L., Singaraja R., Ellerby L., Savill J., Roy S., Leavitt B., Cattaneo E., Hackam A., Sharp A., Thornberry N., Nicholson D.W., Bredesen D.E., Hayden M.R., Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells, J. Biol. Chem., 275: 19831–8, 2000. [DOI] [PubMed] [Google Scholar]
  • 79. Gervais F.G., Singaraja R., Xanthoudakis S., Gutekunst C.A., Leavitt B.R., Metzler M., Hackam A.S., Tam J., Vaillancourt J.P., Houtzager V., Rasper D.M., Roy S., Hayden M.R., Nicholson D.W., Recruitment and activation of caspase‐8 by the Huntingtin‐interacting protein Hip‐1 and a novel partner Hippi, Nat. Cell Biol., 4: 95–105, 2002. [DOI] [PubMed] [Google Scholar]
  • 80. Zhu S., Stavrovskaya I.G., Drozda M., Kim B.Y., Ona V., Li M., Sarang S., Liu A.S., Hartley D.M., Wu du C., Gullans S., Ferrante R.J., Przedborski S., Kristal B.S., Friedlander R.M., Minocycline inhibits cytochrome c. release and delays progression of amyotrophic lateral sclerosis in mice, Nature, 417: 74–78, 2002. [DOI] [PubMed] [Google Scholar]
  • 81. Guegan C., Vila M., Teissman P., Chen C., Onteniente B., Li M., Friedlander R.M., Przedborski S., Instrumental activation of bid by caspase‐1 in a transgenic mouse model of ALS, Mol. Cell Neurosci., 20: 553–562, 2002. [DOI] [PubMed] [Google Scholar]
  • 82. Mochizuki H., Hayakawa H., Migita M., Shibata M., Tanaka R., Suzuki A., Shimo‐Nakanishi Y., Urabe T., Yamada M., Tamayose K., Shimada T., Miura M., Mizuno Y., An AAV‐derived Apaf‐1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease, Proc. Natl. Acad. Sci. USA, 98: 10918–10923, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. Yakovlev A.G., Ota K., Wang G., Movsesyan V., Bao W.L., Yoshihara K., Faden A.I., Differential expression of apoptotic protease‐activating factor‐1 and caspase‐3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury, J. Neurosci., 21: 7439–7446, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Chapman P.F., White G.L., Jones M.W., Cooper‐Blacketer D., Marshall V.J., Irizarry M., Younkin L., Good M.A., Bliss T.V., Hyman B.T., Younkin S.G., Hsiao K.K., Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice, Nat. Neurosci., 2: 271–276, 1999. [DOI] [PubMed] [Google Scholar]
  • 85. Carter R.J., Lione L.A., Humby T., Mangiarini L., Mahal A., Bates G.P., Dunnett S.B., Morton A.J., Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation, J. Neurosci., 19: 3248–3257, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Hansson O., Petersen A., Leist M., Nicotera P., Castilho R.F., Brundin P., Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid‐induced striatal excitotoxicity, Proc. Natl. Acad. Sci. USA, 96: 8727–8732, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Ivins K.J., Bui E.T., Cotman C.W., Beta‐amyloid induces local neurite degeneration in cultured hippocampal neurons: evidence for neuritic apoptosis, Neurobiol. Dis., 5: 365–378, 1998. [DOI] [PubMed] [Google Scholar]
  • 88. Ankarcrona M., Dypbukt J.M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton S.A., Nicotera P., Glutamate‐induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function, Neuron, 15: 961–973, 1995. [DOI] [PubMed] [Google Scholar]
  • 89. Volbracht C., Leist M., Kolb S.A., Nicotera P., Apoptosis in caspase‐inhibited neurons, Mol. Med., 7: 36–48, 2001. [PMC free article] [PubMed] [Google Scholar]

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