Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription

  • W. G. Tatton
  • R. M. E. Chalmers-Redman
  • W. Y. H. Ju
  • J. Wadia
  • N. A. Tatton


Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer’s disease, Parkinson’s disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction.


Amyotrophic Lateral Sclerosis PC12 Cell Mitochondrial Membrane Potential Spinal Muscular Atrophy Facial Motoneuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akao Y, Otsuki U, Kataoka S, Ito Y, Tsujimoto Y (1994) Multiple subcellular localization of bcl-2: detection in nuclear outer membrane, endoplasmic reticulum membrane, and mitochondrial membranes. Cancer Res 54: 2468-2471PubMedGoogle Scholar
  2. Altman J (1992) Programmed cell death: the paths to suicide. TINS 15: 278–280PubMedGoogle Scholar
  3. Anglade P, Michel P, Marquez J, Mouatt-Prient A, Ruberg M, Hirsch EC, et al (1995) Apoptotic degeneration of nigral dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci 21: 489–493Google Scholar
  4. Ansari KS, Yu PH, Kruck TX, Tatton WG (1993) Rescue of axotomized immature rat-facial motoneurons by R(-)-deprenyl: stereospecificity and independence from monoamine oxidase inhibition. J Neurosci 13: 4042–4053PubMedGoogle Scholar
  5. Baffy G, Miyashita T, Williamson JR, Reed JC (1993) Apoptosis induced by withdrawal of Interleukin 3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with partitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem 268: 6511–6519PubMedGoogle Scholar
  6. Barber AJ, Paterson IA, Gelowitz DL, Voll CL (1993) Deprenyl protects rat hippocampal pyramidal cells from ischemic insult. Soc Neurosci Abstr 19: 1646Google Scholar
  7. Baringaga M (1994) Neurotrophic factors enter the clinic. Science 264: 772–774CrossRefGoogle Scholar
  8. Batistatou A, Merry DW, Korsmeyer SJ, Greene LA (1993) Bcl-2 affects survival but not neuronal differentiation of PC12 cells. J Neurosci 13: 4422–4428PubMedGoogle Scholar
  9. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 31: 119–130PubMedCrossRefGoogle Scholar
  10. Beal MF, Hyman T, Koroshetz W (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? TINS 16: 125–131PubMedGoogle Scholar
  11. Behl C, Hovey L, Krajewski S, Schubert D, Reed JC (1993) Bcl-2 prevents killing of neuronal cells by glutamate but not by amyloid beta protein. Biochem Biophys Res Commun 197: 949–956PubMedCrossRefGoogle Scholar
  12. Berkelaar M, Clarke DB, Wang YC, Bray GM, Aguayo AJ (1994) Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci 14: 4368–4374PubMedGoogle Scholar
  13. Bernardes CF, Meyer-Fernandes JR, Basseres DS, Castilho RF, Vercesi AE (1994) Ca(2+)-dependent permeabilization of the inner mitochondrial membrane by 4,4′-diisothicyana-tostilbene-2,2′-disulfonic acid (DIDS). Biochim Biophys Acta 1188: 93–100PubMedCrossRefGoogle Scholar
  14. Biagini G, Zoli M, Fuxe K, Agnati LF (1993) L-Deprenyl increases GFAP immunoreactivity selectively in activated astrocytes in rat brain. Neuroreport 4: 955–958PubMedCrossRefGoogle Scholar
  15. Biagini G, Frasoldati A, Fuxe K, Agnati LF (1994) The concept of astrocyte-kinetic drug in the treatment of neurodegenerative diseases: evidence for L-Deprenyl-induced activation of reactive astrocytes. Neurochem 25: 17–22CrossRefGoogle Scholar
  16. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995a) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92: 7162–7166PubMedCrossRefGoogle Scholar
  17. Bonfoco E, Ceccatelli S, Manzo L, Nicotera P (1995b) Colchicine induces apoptosis in cerebellar granule cells. Exp Cell Res 218: 189–200PubMedCrossRefGoogle Scholar
  18. Brouillet E, Jenkins BG, Hyman BT, Ferrante RJ, Kowall NW, Srivastave R, Roy DS, BRR, Beal MF (1993) Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitropropionic acid. J Neurochem 60: 356–359PubMedCrossRefGoogle Scholar
  19. Brugg B, Michel PP, Agid Y, Ruberg M (1996) Ceramide induces apoptosis in cultured mesencephalic neurons. J Neurochem 66: 733–739PubMedCrossRefGoogle Scholar
  20. Buchi ER (1992) Cell death in the rat retina after a pressure-induced ischaemia-reperfusion insult: an electron microscopic study. I. Ganglion cell layer and inner nuclear. Exp Eye Res 55: 605–613PubMedCrossRefGoogle Scholar
  21. Buys YM, Trope GE, Tatton WG (1995) (-)-Deprenyl increases the survival of retinal ganglion cells after optic nerve crush. Curr Eye Res 14: 119–126PubMedCrossRefGoogle Scholar
  22. Carrillo MC, Kanai S, Nokubo M, Ivy GO, Sato Y, Kitani K (1992) (-)-Deprenyl increases activities of superoxide dismutase and catalase in striatum but not in hippocampus. The sex and age-related differences in the optimal dose in the rat. Exp Neurol 116: 286–294PubMedCrossRefGoogle Scholar
  23. Chacon E, Reece JM, Nieminen AL, Zahrebelski G, Herman B, Lemasters JJ (1994) Distribution of electrical potential, pH, free Ca2+, and volume inside cultured adult rabbit cardiac myocytes during chemical hypoxia: a multiparameter digitized confocal microscopic study. Biophys 66: 942–952CrossRefGoogle Scholar
  24. Chang G-Q, Hao Y, Wong F (1993) Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 11: 595–605PubMedCrossRefGoogle Scholar
  25. Chen-Levy S, Cleary ML (1990) Membrane topology of the Bcl-2 proto-oncogenic protein demonstrated in vitro. J Biol Chem 265: 4929–4933PubMedGoogle Scholar
  26. Choi DW, Rotham SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Ann Rev Neurosci 13: 171–182PubMedCrossRefGoogle Scholar
  27. Copani A, Bruno VM, Barresi V, Battaglia G, Condorelli DF, Nicoletti F (1995) Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture. J Neurochem 64: 101–108PubMedCrossRefGoogle Scholar
  28. Cote C, Boulet D, Poirier J (1990) Expression of the mammalian mitochondrial genome-role for membrane potential in the production of mature translational products. J Biol Chem 265: 7532–7538PubMedGoogle Scholar
  29. Cotman CW, Anderson AJ (1995) A potential role for apoptosis in neurodegeneration and Alzheimer’s disease. Mol Neurobiol 10: 19–45PubMedCrossRefGoogle Scholar
  30. Cotman CW, Whittemore ER, Watt JA, Anderson AJ, Loo DT (1994) Possible role of apoptosis in Alzheimer’s disease. Ann NY Acad Sci 747: 36–49PubMedCrossRefGoogle Scholar
  31. Csernansky CA, Canzoniero LM, Sensi SL, Yu SP, Choi DW (1994) Delayed application of aurintricarboxylic acid reduces glutamate-induced. J Neurosci Res 38: 101–108PubMedCrossRefGoogle Scholar
  32. Dai-Canto RC, Gurney ME (1994) Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 145: 1271–1279Google Scholar
  33. Deckwerth TL, Johnson EM (1993) Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J Cell Biol 123: 1207–1222PubMedCrossRefGoogle Scholar
  34. Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzgeldt B, Roos RP (1993) Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261: 1047–1051PubMedCrossRefGoogle Scholar
  35. Dessi F, Ben-Ari Y, Charriaut-Marlangue C (1994) Increased synthesis of specific proteins during glutamate-induced neuronal death in cerebellar culture. Brain Res 654: 27–33PubMedCrossRefGoogle Scholar
  36. Dessi F, Pollard H, Moreau J, Ben Ari Y, Charriaut-Marlangue C (1995) Cytosine arabinoside induces apoptosis in cerebellar neurons in culture. J Neurochem 64:1980–1987PubMedCrossRefGoogle Scholar
  37. Dipasquale B, Marini AM, Youle RJ (1991) Apoptosis and DNA degradation induced by 1-methyl-4-phenyl-tetrahydropyridine. BiochemBiophys Res Commun 181:1442–1448CrossRefGoogle Scholar
  38. Dragunow M, Young D, Hughes P, MacGibbon G, Lawlor P, Singleton K (1993) Is c-Jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? Mol Brain Res 18: 347–352PubMedCrossRefGoogle Scholar
  39. Dragunow M, Faull RL, Lawlor P, Beilharz EJ, Singleton K, Walker EB, et al (1995) In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobes. Neuroreport 6: 1053–1057PubMedCrossRefGoogle Scholar
  40. Dubois-Dauphin MFH, Tsujimoto Y, Huatte J, Martinou JC (1994) Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death. Proc Natl Acad Sei USA 91: 3309–3313CrossRefGoogle Scholar
  41. Eisen A, Krieger C (1993) Pathogenic mechanisms in sporadic amyotrophic lateral sclerosis. Can J Neurol Sei 20: 286–296Google Scholar
  42. Ekblom J, Jossan SS, Ebendal T, Soderstrom S, Oreland L, Aquilonius S-M (1993) Expression of mRNAs for neurotrophins and members of the Trk family in the rat brain after treatment with L-deprenyl. Acta Neurol Scand 84 [Suppl]: 79–86Google Scholar
  43. Farinelli SE, Greene LA (1996) Cell cycle blockers mimosine, ciclopirox and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J Neurosci 16: 1150–1162PubMedGoogle Scholar
  44. Finch CE (1993) Neuron atrophy during aging: programmed or sporadic? TINS 16:104–110PubMedGoogle Scholar
  45. Finnegan KT, Karler R (1992) Role for protein synthesis in the neurotoxic effects of methamphetamine in mice and rats. Br Res 591: 160–164CrossRefGoogle Scholar
  46. Finnegan KT, Skratt JJ, Irwin I, DeLanney LE, Langston JW (1990) Protection against DSP-4 induced neurotoxicity by deprenyl is not related to its inhibition of MAO B. Eur J Pharmacol 184:Google Scholar
  47. Forloni G (1993) beta-Amyloid neurotoxicity. Funct Neurol 8: 211–225PubMedGoogle Scholar
  48. Forloni G, Chiesa R, Smiroldo S, Verga L, Salmona M, Tagliavini F (1993) Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25–35. Neuroreport 4: 523–526PubMedCrossRefGoogle Scholar
  49. Frim DM, Simpson J, Uhler TA, Short MP, Bossi SR, Breakfield XO, Isacson O (1993 a) Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF. J Neurosci Res 35: 452–458PubMedCrossRefGoogle Scholar
  50. Frim DM, Uhler TA, Short MP, Ezzedine ZD, Klagsbrun M, Breakefield XO (1993b) Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxicity. Neuroreport 4: 367–370PubMedCrossRefGoogle Scholar
  51. Garcia VE, Gorczyca W, Darzynkiewicz Z, Sharma SC (1994) Apoptosis in adult retinal ganglion cells after axotomy. J Neurobiol 25: 431–438CrossRefGoogle Scholar
  52. Givol I, Tsarfaty I, Resau J, Rulong S, da Silva PP, Nasioulas G, DuHadaway J, Hughes SH, Ewert DL (1994) Bcl-2 expressed using a retroviral vector is localized primarily in the nuclear membrane and the endoplasmic reticulum of chicken embryo fibroblasts. Cell Growth Differ 5: 419–429PubMedGoogle Scholar
  53. Gobe GC (1994) Apoptosis in brain and gut tissue of mice fed a seed preparation of the cycad Lepidozamia peroffshyana. Biochem Biophys Res Commun 205: 327–333PubMedCrossRefGoogle Scholar
  54. Greenlund LJS, Deckwerth TL, Johnson EM (1995) Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 14: 303–315PubMedCrossRefGoogle Scholar
  55. Gurney ME, Pu H, Chiu AY, Dai-Canto MC, Polchow CY, Alexander DD (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264: 1771–1775CrossRefGoogle Scholar
  56. Hall ED, McCall JM (1994) Therapeutic potential of the lazeroids (21 aminosteroids) in acute CNS trauma, ischemia and subarachnoid hemorrhage. Adv Pharmacol 28: 221–268PubMedCrossRefGoogle Scholar
  57. Hamburger V, Oppenheim RW (1982) Naturally-occurring neuronal death in vertebrates. Neurosci Comment 1: 38–55Google Scholar
  58. Hartley A, Stone JM, Heron C, Cooper JM, Schapira AH (1994) Complex I inhibitors induce dose-dependent apoptosis in PC12 cells. J Neurochem 63: 1987–1990PubMedCrossRefGoogle Scholar
  59. Henderson JT, Seniuk NA, Richardson PM, Gauldie J, Roder JC (1994) Systemic administration of ciliary neurotrophic factor induces cachexia in rodents. J Clin Invest 93: 2632–2638PubMedCrossRefGoogle Scholar
  60. Hengartner MO, Horvitz HR (1994) C. elegans cell survival gene ced-9 encodes a functional homologue of the mammalian proto-oncogene bcl-2. Cell 76: 655–676CrossRefGoogle Scholar
  61. Hennet TG, Bertoni G, Richter C, Peterhans E (1993) Expression of Bcl-2 protein enhances the survival of mouse fibrosarcoid cells in tumor necrosis factor-mediated cytotoxicity. Cancer Res 53: 1456–1460PubMedGoogle Scholar
  62. Hockenbery D, Nuez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336PubMedCrossRefGoogle Scholar
  63. Hockenbery DM, Ottval ZN, Xiao-Ming Y, Korsmeyer SJ (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241–251PubMedCrossRefGoogle Scholar
  64. Iwasaki Y, Ikeda K, Shoijima T, Kobayashi T, Tagaya N, Kinoshita M (1994) Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons. J Neurol Sci 125: 11–13PubMedCrossRefGoogle Scholar
  65. Jacobson MD, Burne JF, King MP, Miyashita T, Reed JC, Raff MC (1993) Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 361: 365–369PubMedCrossRefGoogle Scholar
  66. Janiak F, Leber B, Andrews DW (1994) Assembly of Bcl-2 into microsomal and outer mitochondrial membranes. Biol Chem 269: 9842–9849Google Scholar
  67. Joseph R, Li W, Han E (1993) Neuronal death, cytoplasmic calcium and internucleosomal DNA fragmentation: evidence for DNA fragments being released from cells. Brain Res Mol Brain Res 17: 70–76PubMedCrossRefGoogle Scholar
  68. Johnson EM Jr (1994) Possible role of neuronal apoptosis in Alzheimer’s disease. Neurobiol Aging 15(2): S187–189PubMedCrossRefGoogle Scholar
  69. Ju WYH, Holland DP, Tatton WG (1994) (-)-Deprenyl alters the time course of death of axotomized facial motoneurons and the hypertrophy of neighboring astrocytes in immature rats. Exp Neurol 126: 233–246PubMedCrossRefGoogle Scholar
  70. Kaku DA, Giffard RG, Choi DW (1993) Neuroprotective effects of glutamate antagonists and extracellular acidity. Science 260: 1516–1518PubMedCrossRefGoogle Scholar
  71. Kane DJ, Ord T, Anton R, Bredesen DE (1995) Rapid Communication: Expression of bcl-2 inhibits necrotic neural cell death. J Neurosci Res 40: 269–275PubMedCrossRefGoogle Scholar
  72. Kobayashi Y, Saheki T, Shinozawa T (1994) Induction of PC12 cell death, apoptosis, by a sialoglycopeptide from bovine brain. Biochem Biophys Res Commun 203: 1554–1559PubMedCrossRefGoogle Scholar
  73. Koh JY, Cotman CW (1992) Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonists. Brain Res 587: 233–240PubMedCrossRefGoogle Scholar
  74. Korsmeyer SJ (1992) Bcl-2: an antidote to programmed cell death. Cancer Surveys 15: 105–118PubMedGoogle Scholar
  75. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 4: 327–332PubMedGoogle Scholar
  76. Koutsiliere E, O’Callaghan JFX, Chen T-S, Riederer P, Rausch W-D (1994) Selegiline enhances survival and neurite outgrowth of MPP-treated dopaminergic neurons. Eur J Pharmacol 269: R3-R4CrossRefGoogle Scholar
  77. Langston JW (1994) MPTP Parkinsonism. Mov Disord 9: 3CrossRefGoogle Scholar
  78. Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, et al (1995) Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ. Acta Neuropathol Berl 89: 35–41PubMedCrossRefGoogle Scholar
  79. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier D, Frezal J, Cohen D, Weissenback J, Munnich A, Melki J (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80: 155–165PubMedCrossRefGoogle Scholar
  80. Li XM, Juorio AV, Paterson IA, Zhu MY, Boulton AA (1992) Specific irreversible monoamine oxidase-B inhibitors stimulate gene expression of aromatic L-amino acid decarboxylase in PC12-cells. J Neurochem 59: 2324–2327PubMedCrossRefGoogle Scholar
  81. Li XM, Qi J, Juorio AV, Boulton AA (1993) Reduction in glial fibrillary acidic protein messenger RNA abundance induced by (-)-Deprenyl and other monoamine oxidase B-inhibitors in C6 glioma cells. J Neurochem 61: 1573–1576PubMedCrossRefGoogle Scholar
  82. Linnik MD, Zobrist RH, Hatfield MD (1993) Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 24: 2002–2008PubMedCrossRefGoogle Scholar
  83. Lolley RN, Rong H, Craft CM (1994) Linkage of photoreceptor degeneration by apoptosis with inherited defect in phototransduction. Invest Ophthalmol Vis Sci 35: 358–362PubMedGoogle Scholar
  84. Margolis RL, Chuang DM, Post RM (1994) Programmed cell death: implications for neuropsychiatric disorders. Biol Psychiatry 35: 946–956PubMedCrossRefGoogle Scholar
  85. Mitchell IJ, Lawson S, Moser B, Laidlaw SM, Cooper AJ, Walkinshaw G, et al (1994) Glutamate-induced apoptosis results in a loss of striatal neurons in the parkinsonian rat. Neurosci 63: 1–5CrossRefGoogle Scholar
  86. Mochizuki H, Nakamura N, Nishi K, Mizuno Y (1994) Apoptosis is induced by 1-methyl-4-phenylpyridinium ion (MPP+) in ventral mesencephalic-striatal co-culture in rat. Neurosci Lett 170: 191–194PubMedCrossRefGoogle Scholar
  87. Monaghan P, Robertson D, Amos AS, Dyer MJS, Mason DY, Greaves MF (1992) Ultrastructural localization of Bcl-2 protein. J Histochem Cytochem 40: 1819–1825PubMedCrossRefGoogle Scholar
  88. Montpied P, Weiler M, Paul SM (1993) N-methyl-D-aspartate receptor agonists decrease protooncogene bcl-2 mRNA expression in cultured rat cerebellar granule neurons. Biochem Biophys Res Commun 195: 623–629PubMedCrossRefGoogle Scholar
  89. Mou L, Miller H, Li J, Wang E, Chalifour L (1994) Improvements to differential display method for gene analysis. Biochem Biophys Res Comm 199: 564–569PubMedCrossRefGoogle Scholar
  90. Muller WE, Schroder HC, Ushijima H, Dapper J, Bormann J (1992) gp120 of HIV-1 induces apoptosis in rat cortical cell cultures: prevention by memantine. Eur J Pharmacol 226: 209–214PubMedCrossRefGoogle Scholar
  91. Mutoh T, Tokuda A, Marini AM, Fujiki N (1994) 1-Methyl-4-phenylpyridinium kills differentiated PC12 cells with a concomitant change in protein phosphorylation. Br Res 661: 51–55CrossRefGoogle Scholar
  92. Newmeyer DD, Farschon DM, Reed JC (1994) Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 79: 353–364PubMedCrossRefGoogle Scholar
  93. Nguyen M, Branton PE, Walton PA, Oltvai ZN, Korsmeyer SJ, Shore GC (1994) Role of membrane anchor domain of Bcl-2 in suppression of apoptosis caused by E1B-defective adenovirus. J Biol Chem 269: 16521–16524PubMedGoogle Scholar
  94. Oh C, Murray B, Bhattacharya N, Holland D, Tatton WG (1994) (-)-Deprenyl alters the survival of adult facial motoneurons after axotomy: increases in vulnerable C57BL strain but decreases in Mnd mutants. J Neurosci Res 38:Google Scholar
  95. Olanow CW (1993) A radical hypothesis for neurodegeneration. TINS 16: 439–444PubMedGoogle Scholar
  96. Oltvai ZN, Korsmeyer SJ (1994) Checkpoints of dueling dimers foil death wishes. Cell 79: 189–192PubMedCrossRefGoogle Scholar
  97. Oltvai Z, Milliman C, Korsmeyer SJ (1993) Bcl-2 heterodimers in vivo with a conserved homologue, Bax, that accelerates programmed cell death. Cell 74: 609–619PubMedCrossRefGoogle Scholar
  98. Pender MP, Nguyen KB, McCombe PA, Kerr JFR (1991) Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci 104: 81–87PubMedCrossRefGoogle Scholar
  99. Petito CK, Roberts B (1995) Evidence of apoptotic cell death in HIV encephalitis (see comments). Am J Pathol 146: 1121–1130PubMedGoogle Scholar
  100. Portera CC, Sung CH, Nathans J, Adler R (1994) Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA 91: 974–978CrossRefGoogle Scholar
  101. Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 15: 3775–3787PubMedGoogle Scholar
  102. Price DL, Martin LJ, Clatterbuck RE, Koliatsos VE, Sisodia SS, Walker LC, Cork LC (1992) Neuronal degeneration in human diseases and animal models. J Neurobiol 23: 1277–1294PubMedCrossRefGoogle Scholar
  103. Rabacchi SA, Bonfanti L, Liu XH, Maffei L (1994)Apoptotic cell death induced by optic nerve lesion in the neonatal rat. J Neurosci 14: 5292–5301PubMedGoogle Scholar
  104. Rabizadeh S, Bitler CM, Butcher LL, Bredesen DE (1994) Expression of the low-affinity nerve growth factor receptor enhances beta-amyloid peptide toxicity. Proc Natl Acad Sci USA 91: 10703–10706PubMedCrossRefGoogle Scholar
  105. Reed JC (1994) Bcl-2 and the regulation of programmed cell death. J Cell Biol 124: 1–6PubMedCrossRefGoogle Scholar
  106. Richter C (1993) Pro-oxidants and mitochondrial Ca2+: their relationship to apoptosis and oncogenesis. FEBS Letts 325: 104–107CrossRefGoogle Scholar
  107. Richter C, Frei B (1988) Ca2+ release from mitochondria induced by prooxidants. Free Rad Biol Med 4: 365–375PubMedCrossRefGoogle Scholar
  108. Richter C, Kass GEN (1991) Oxidative stress in mitochondria: its relationship to cellular Ca2+ homeostasis, cell death, proliferation and differentiation. Chem Biol Interact 77: 1–23PubMedCrossRefGoogle Scholar
  109. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati P, Donaldson A, Goto J, O’Regan JP, Deng HK, Gusella JS, Horvitz HR, Brown RH (1994) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62CrossRefGoogle Scholar
  110. Rosenbaum DM, Michaelson M, Batter DK, Doshi P, Kessler JA (1994) Evidence for hypoxia-induced, programmed cell death of cultured neurons. Ann Neurol 36: 864–870PubMedCrossRefGoogle Scholar
  111. Roy E, Bedard PJ (1993) Deprenyl increases survival of rat fetal nigral neurones in culture. Neuroreport 4: 1183–1186PubMedGoogle Scholar
  112. Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S (1995) The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80: 167–178PubMedCrossRefGoogle Scholar
  113. Rukenstein A, Rydel RE, Greene LA (1991) Multiple agents rescue PC12 cells from serumfree cell death by translation- and transcription-independent mechanisms. J Neurosci 11: 2552–2563PubMedGoogle Scholar
  114. Salo PT, Tatton WG (1992) Deprenyl reduces the death of motoneurons caused by axotomy. J Neurosci Res 31: 394–400PubMedCrossRefGoogle Scholar
  115. Samples SD, Dubinsky JM (1993) Aurintricarboxylic acid protects hippocampal neurons from glutamate. J Neurochem 61: 382–385PubMedCrossRefGoogle Scholar
  116. Schapira AV (1994) Mechanisms of cell death in Parkinson’s disease. Mov Disord 9: 2CrossRefGoogle Scholar
  117. Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W (1992) Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. J Biol Chem 267: 5317–5323PubMedGoogle Scholar
  118. Sengstock GJ, Olanow CW, Dunn AJ, Arendash GW (1992) Iron induces degeneration of nigrostriatal neurons. Brain Res Bull 28: 645–649PubMedCrossRefGoogle Scholar
  119. Seniuk NA, Henderson JT, Tatton WG, Roder JC (1994) Increased CNTF gene expression in process bearing astrocytes following injury is augmented by R(-)-deprenyl. J Neurosci Res 37:Google Scholar
  120. Shahinfar S, Edward DP, Tso MO (1991) A pathologic study of photoreceptor cell death in retinal photic injury. Curr Eye Res 10: 47–59PubMedCrossRefGoogle Scholar
  121. Silveira LC, Russelakis CM, Perry VH (1994) The ganglion cell response to optic nerve injury in the cat: differential responses revealed by neurofibrillar staining. J Neurocytol 23: 75–86PubMedCrossRefGoogle Scholar
  122. Slater AF, Nobel CS, Orrenius S (1995) The role of intracellular oxidants in apoptosis. Biochim Biophys Acta 1271: 59–62PubMedGoogle Scholar
  123. Smale G, Nichols NR, Brady DR, Finch CE, Horton WE Jr (1995) Evidence for apoptotic cell death in Alzheimer’s disease. Exp Neurol 133: 225–230PubMedCrossRefGoogle Scholar
  124. Smets LA, Van den Berg J, Acton D, Top B, Van Rooij H, Verwijs-Janssen M (1994) Bcl-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis. Blood 84: 1613–1619PubMedGoogle Scholar
  125. Steinberg RH (1994) Survival factors in retinal degenerations. Curr Opin Neurobiol 4: 515–524PubMedCrossRefGoogle Scholar
  126. Su JH, Anderson AJ, Cummings BJ, Cotman CW (1994) Immunohistochemical evidence for apoptosis in Alzheimer’s disease. Clin Neurosci Neuropathol 5: 2529–2533Google Scholar
  127. Takayama S, Takaaki S, Kajewski S, Kochel K, Irie S, Millan JA, Reed JC (1995) Cloning and functional analysis of BAG-1: a novel Bcl-2 binding protein with anti-cell death activity. Cell 80: 279–284PubMedCrossRefGoogle Scholar
  128. Tatton WG (1993) Selegiline ((-)-deprenyl) can mediate neuronal rescue rather than neuronal protection. Mov Disord 8Google Scholar
  129. Tatton WG, Greenwood CE (1991) Rescue of dying neurons: a new action for Deprenyl in MPTP parkinsonism. J Neurosci Res 30: 666–672PubMedCrossRefGoogle Scholar
  130. Tatton WG, Seniuk NA, Ju WYH, Ansari KS (1993) Reduction of nerve cell death by deprenyl without monoamine oxidase inhibition. In: Leiberman A, Olanow W, You-dim MBH, Tipton K (eds) Monoamine oxidase inhibitors in neurological diseases. Raven Press, New York, pp 217–248Google Scholar
  131. Tatton WG, Ju WYL, Holland DP, Tai CE, Kwan MM (1994) (-)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis. J Neurochem 63: 1572–1574PubMedCrossRefGoogle Scholar
  132. Thiffault C, Aumont N, Quirion R, Poirier J (1994) Antioxidant enzymes in an animal model of Parkinson’s disease. Can J Physiol Pharmacol 72: 592Google Scholar
  133. Thomas LB, Gates DJ, Richfield EK, Schweitzer JB, Steindler DA (1995) DNA end labeling (TUNEL) in Huntingtons disease and other neuropathological conditions. Exp Neurol 133: 265–272PubMedCrossRefGoogle Scholar
  134. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456–1462PubMedCrossRefGoogle Scholar
  135. Tipton KF, Singer TP (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem 61: 1191–1207PubMedCrossRefGoogle Scholar
  136. Troy CM, Shelanski ML (1994) Down-regulation of copper/zinc superoxide dismutase causes apoptotic death. Proc Natl Acad Sci USA 91: 6384–6387PubMedCrossRefGoogle Scholar
  137. Tso MO, Zhang C, Abler AS, Chang CJ, Wong F, Chang GQ, Lam TT (1994) Apoptosis leads to photoreceptor degeneration in inherited retinal dystrophy of RCS rats. Invest Ophthalmol Vis Sci 35: 2693–2699PubMedGoogle Scholar
  138. Tsuda T, Munthasser S, Fraser PE, Percy ME, Rainero I, Vaula G, Pinessi L, Bergamini L, Vignocchi G, Crapper McLachlan DR, Tatton WG, St. George-Hyslop P (1994) Analysis of the functional effects of a mutation in SOD1 associated with familial Amyotrophic Lateral Sclerosis. Neuron 13: 727–736Google Scholar
  139. van de Water B, Zoeteweij JP, deBont HJ, Mulder GJ, Nagelkerke JF (1994) Role of mitochondrial Ca2+ in the oxidative stress-induced dissipation of the mitochondrial membrane potential. Studies in isolated proximal tubular cells using the nephrotoxin 1,2-dichlorovinyl-L-cysteine. J Biol Chem 269: 14546–14552PubMedGoogle Scholar
  140. Vayssiere JL, Petit PX, Risler Y, Mignotte B (1994) Commitment to apoptosis is associated with changes in mitochondrial biogenesis and activity in cell lines conditionally immortalized with simian virus 40. Proc Natl Acad Sci USA 91: 11752–11760PubMedCrossRefGoogle Scholar
  141. Walkinshaw G, Waters CM (1994) Neurotoxin-induced cell death in neuronal PC12 cells is mediated by induction of apoptosis. Neurosci 63: 975–987CrossRefGoogle Scholar
  142. Werth JL, Thayer SA (1994) Mitochondria buffer physiological Ca2+ loads in cultured rat dorsal root ganglion neurons. J Neurosci 14: 348–356PubMedGoogle Scholar
  143. Wolvetang EF, Johnson KL, Krauer K, Ralph SJ, Linnane AW (1994) Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett 339: 40–44PubMedCrossRefGoogle Scholar
  144. Wu R-M, Chiueh CC, Pert A, Murphy DL (1993) Apparent antioxidant effect of 1-deprenyl on hydroxyl radical formation and nigral injury elicited by MPP+ in vivo. Eur J Pharmacol 243: 241–248PubMedCrossRefGoogle Scholar
  145. Wu RM, Murphy DL, Chiueh CC (1995) Neuronal protective and rescue effects of deprenyl against MPP+ dopaminergic toxicity. J Neural Transm 100: 53–61CrossRefGoogle Scholar
  146. Wyllie AH, Morris RG, Smith AL, Dunlop D (1984) Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol 142: 67–77PubMedCrossRefGoogle Scholar
  147. Yan GM, Ni B, Weller M, Wood KA, Paul SM (1994) Depolarization or glutamate receptor activation blocks apoptotic cell death. Brain Res 656: 43–51PubMedCrossRefGoogle Scholar
  148. Yang E, Zha J, Jockei J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-xL and Bcl-2 displaces Bax and promotes cell death. Cell 80: 285–291PubMedCrossRefGoogle Scholar
  149. Yin X-M, Oltvai ZN, Korsmeyer SJ (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369: 321–323PubMedCrossRefGoogle Scholar
  150. Yoshiyama Y, Yamada T, Asanuma K, Asahi T (1994) Apoptosis related antigen, Le(Y) and nick-end labeling are positive in spinal motor neurons in amyotrophic lateral sclerosis. Acta Neuropathol Berl 88: 207–211PubMedCrossRefGoogle Scholar
  151. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, et al (1995a) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182: 367–377PubMedCrossRefGoogle Scholar
  152. Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiere J-L, Petit PX, Kroemer G (1995 b) Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 181: 1661–1672PubMedCrossRefGoogle Scholar
  153. Zhang F, Richardson PM, Holland DP, Guo G, Tatton WG (1995) CNTF or (-)-deprenyl in immature rats: survival of axotomized facial motoneurons and weight loss. J Neurosci Res 40: 564–570PubMedCrossRefGoogle Scholar
  154. Zhong LT, Sarafian T, Kane DJ, Charles AC, Mah SP, Edwards RH, Bredesen DE (1993) bcl-2 inhibits death of central neural cells induced by multiple agents. PNAS 90: 4533– 4537PubMedCrossRefGoogle Scholar
  155. Ziv I, Melamed E, Nardi N, Luria D, Achiron A, Offen D, Barzilai A (1994) Dopamine induces apoptosis-like cell death in cultured chick sympathetic. Neurosci Lett 170: 136–140PubMedCrossRefGoogle Scholar
  156. Zsnagy I, Steiber J, Jeney (1995) Induction of age pigment accumulation in the brain cells of young male rats through iron-injection into the cerebrospinal fluid. Gerontology 41: 145–156CrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1997

Authors and Affiliations

  • W. G. Tatton
    • 1
    • 2
    • 4
  • R. M. E. Chalmers-Redman
    • 1
    • 4
  • W. Y. H. Ju
    • 1
  • J. Wadia
    • 1
  • N. A. Tatton
    • 3
    • 4
  1. 1.Department of Physiology/BiophysicsDalhousie UniversityHalifaxCanada
  2. 2.Department of PsychologyDalhousie UniversityHalifaxCanada
  3. 3.Department of PharmacologyDalhousie UniversityHalifaxCanada
  4. 4.The Institute for NeuroscienceDalhousie UniversityHalifaxCanada

Personalised recommendations