Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk

Journal of Neuroscience

Volumn 29, Issue 7, 2009, Pages 1987-1997

  Young, Jessica E ^a   Garden, Gwenn A ^a   Martinez, Refugio A ^a   Tanaka, Fumiaki ^c   Sandoval, C Miguel ^c   Smith, Annette C ^a   Sopher, Bryce L ^a   Lin, Amy ^d   Fischbeck, Kenneth H ^c   Ellerby, Lisa M ^d   Morrison, Richard S ^a,b   Taylor, J Paul ^e,g   La Spada, Albert R ^a,f  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^c NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE   (United States)

^d BUCK INSTITUTE FOR RESEARCH ON AGING   (United States)

^e UNIVERSITY OF PENNSYLVANIA   (United States)

^f UNIVERSITY OF WASHINGTON MEDICAL CENTER   (United States)

^g ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

Author keywords

Apoptosis; Bax; DP5; Polyglutamine; Spinal and bulbar muscular atrophy; Truncation

Indexed keywords

ANDROGEN RECEPTOR; BH3 PROTEIN; POLYGLUTAMINE; PROTEIN BAX; PROTEIN C JUN; STRESS ACTIVATED PROTEIN KINASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; BRAIN CELL; BRAIN NERVE CELL; CELL DEATH; CYTOSOL; KENNEDY DISEASE; MOTONEURON; MOTOR NEURON DISEASE; MOUSE; NERVE DEGENERATION; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; TRANSGENIC MOUSE; UPREGULATION;

ANIMALS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; BCL-2-ASSOCIATED X PROTEIN; CELL LINE; CELLS, CULTURED; CENTRAL NERVOUS SYSTEM; JNK MITOGEN-ACTIVATED PROTEIN KINASES; MICE; MICE, TRANSGENIC; MUSCULAR ATROPHY, SPINAL; NEURONS; NEUROPEPTIDES; PEPTIDE FRAGMENTS; PEPTIDES; PROTEIN FOLDING; RECEPTORS, ANDROGEN; SIGNAL TRANSDUCTION; TRINUCLEOTIDE REPEAT EXPANSION;

EID: 60849095522     PISSN: 02706474     EISSN: 02706474     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.4072-08.2009     Document Type: Article

References (80)

1. Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Yoshida M, Hashizume Y, Sobue G (2005) Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 128:659-670.
2. Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98:13681-13686.
3. Bogoyevitch MA, Boehm I, Oakley A, Ketterman AJ, Barr RK (2004) Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim Biophys Acta 1697:89-101.
4. Chevalier-Larsen ES, O'Brien CJ, Wang H, Jenkins SC, Holder L, Lieberman AP, Merry DE (2004) Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy. J Neurosci 24:4778-4786.
5. Chiariello M, Marinissen MJ, Gutkind JS (2000) Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol 20:1747-1758.
6. Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY, Tsai SR, Kakizuka A, Wang HL (2006) Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. Neurobiol Dis 21:333-345.
7. Colomer Gould VF, Goti D, Pearce D, Gonzalez GA, Gao H, Bermudez de Leon M, Jenkins NA, Copeland NG, Ross CA, Brown DR (2007) Amu-tant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiol Dis 27:362-369.
8. Conforti L, Adalbert R, Coleman MP (2007) Neuronal death: where does the end begin? Trends Neurosci 30:159-166.
9. Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, Dawson VL, Dawson TM, Ross CA (1998) Truncated N-terminal fragments of huntingtin with ex-pandedglutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet 7:783-790.
10. Darrington RS, Butler R, Leigh PN, McPhaul MJ, Gallo JM (2002) Ligand-dependent aggregation of polyglutamine-expanded androgen receptor in neuronal cells. Neuroreport 13:2117-2120.
11. Donovan N, Becker EB, Konishi Y, Bonni A (2002) JNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem 277:40944-40949.
12. Ellerby LM, Andrusiak RL, Wellington CL, Hackam AS, Propp SS, Wood JD, Sharp AH, Margolis RL, Ross CA, Salvesen GS, Hayden MR, Bredesen DE (1999a) Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. J Biol Chem 274:8730-8736.
13. Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR, Trifiro MA, Pinsky L, Wellington CL, Salvesen GS, Hayden MR, Bredesen DE (1999b) Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem 72:185-195.
14. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA, Bredesen DE (2006) 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.
15. Garden GA, Libby RT, Fu YH, Kinoshita Y, Huang J, Possin DE, Smith AC, Martinez RA, Fine GC, Grote SK, Ware CB, Einum DD, Morrison RS, Ptacek LJ, Sopher BL, La Spada AR (2002) Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous Purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J Neurosci 22:4897-4905.
16. Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bromm M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR (1996) Cleavage of huntingtin by apopain, a proapop-totic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 13:442-449.
17. Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC, Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MR (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125:1179-1191.
18. Haacke A, Broadley SA, Boteva R, Tzvetkov N, Hartl FU, Breuer P (2006) Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum Mol Genet 15:555-568.
19. Harris CA, Johnson EM Jr (2001) BH3-only Bcl-2 family members are co-ordinately regulated by the JNK pathway and require Bax to induce apo-ptosis in neurons. J Biol Chem 276:37754-37760.
20. Holzberg D, Knight CG, Dittrich-Breiholz O, Schneider H, Dorrie A, Hoffmann E, Resch K, Kracht M (2003) Disruption of the c-JUN-JNK complex by a cell-permeable peptide containing the c-JUN delta domain induces apoptosis and affects a distinct set of interleukin-1-induced inflammatory genes. J Biol Chem 278:40213-40223.
21. Huang DC, Strasser A (2000) BH3-only proteins-essential initiators of ap-optotic cell death. Cell 103:839-842.
22. Iavarone C, Catania A, Marinissen MJ, Visconti R, Acunzo M, Tarantino C, Carlomagno MS, Bruni CB, Gutkind JS, Chiariello M (2003) The platelet-derived growth factor controls c-myc expression through a JNK-and AP-1-dependent signaling pathway. J Biol Chem 278:50024-50030.
23. Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13:196-202.
24. Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M (1997) Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 272:18842-18848.
25. Imaizumi K, Morihara T, Mori Y, Katayama T, Tsuda M, Furuyama T, Wanaka A, Takeda M, Tohyama M (1999) The cell death-promoting gene DP5, which interacts with the BCL2 family, is induced during neu-ronal apoptosis following exposure to amyloid beta protein. J Biol Chem 274:7975-7981.
26. Imaizumi K, Benito A, Kiryu-Seo S, Gonzalez V, Inohara N, Lieberman AP, Kiyama H, Nuñez G, Leiberman AP (2004) Critical role for DP5/Hara-kiri, a Bcl-2 homologydomain 3-onlyBcl-2 familymember, in axotomy-induced neuronal cell death. J Neurosci 24:3721-3725.
27. Inohara N, Ding L, Chen S, Nüñez G (1997) harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 16:1686-1694.
28. Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Sang C, Koba-yashi Y, Doyu M, Sobue G (2002) Testosterone reduction prevents phe-notypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35:843-854.
29. Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 18:671-680.
30. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270:96-99.
31. Kobayashi Y, Miwa S, Merry DE, Kume A, Mei L, Doyu M, Sobue G (1998) Caspase-3 cleaves the expanded androgen receptor protein ofspinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner. Biochem Biophys Res Commun 252:145-150.
32. Kostic V, Jackson-Lewis V, de Bilbao F, Dubois-Dauphin M, Przedborski S (1997) Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 277:559-562.
33. Kouroku Y, Fujita E, Jimbo A, Kikuchi T, Yamagata T, Momoi MY, Komi-nami E, Kuida K, Sakamaki K, Yonehara S, Momoi T (2002) Polyglu-tamine aggregates stimulate ER stress signals and caspase-12 activation. Hum Mol Genet 11:1505-1515.
34. La Spada AR, Taylor JP (2003) Polyglutamines placed into context. Neuron 38:681-684.
35. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77-79.
36. Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G (1998a) Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 44:249-254.
37. Li M, Nakagomi Y, Kobayashi Y, Merry DE, Tanaka F, Doyu M, Mitsuma T, Hashizume Y, Fischbeck KH, Sobue G (1998b) Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 153:695-701.
38. Li M, Chevalier-Larsen ES, Merry DE, Diamond MI (2007) Soluble andro-gen receptor oligomers underlie pathology in a mouse model of spino-bulbar muscular atrophy. J Biol Chem 282:3157-3164.
39. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, WangX (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479-489.
40. Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenera-tive diseases. Cell Death Differ 13:385-392.
41. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, PietraC, Huarte J (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017-1030.
42. Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120-129.
43. Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KH (1998) Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet 7:693-701.
44. Miyashita T, Okamura-Oho Y, Mito Y, Nagafuchi S, Yamada M (1997) Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis. J Biol Chem 272:29238-29242.
45. Morfini G, Pigino G, Szebenyi G, You Y, Pollema S, Brady ST (2006) JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci 9:907-916.
46. Moulder KL, Onodera O, Burke JR, Strittmatter WJ, Johnson EM Jr (1999) Generation of neuronal intranuclear inclusions by polyglutamine-GFP: analysis of inclusion clearance and toxicityas afunction of polyglutamine length. J Neurosci 19:705-715.
47. Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, Kanazawa I (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10:1441-1448.
48. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H (2002) ASK1 is essential for endoplasmic reticu-lum stress-induced neuronal cell death triggered by expanded polyglu-tamine repeats. Genes Dev 16:1345-1355.
49. Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592-603.
50. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS, Li XJ, Stieg PE, Yuan J, Penney JB, Young AB, Cha JH, Fried-lander RM (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399:263-267.
51. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:859-863.
52. Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19:333-344.
53. Perrelet D, Ferri A, Liston P, Muzzin P, Korneluk RG, Kato AC (2002) IAPs are essential for GDNF-mediated neuroprotective effects in injured motor neurons in vivo. Nat Cell Biol 4:175-179.
54. Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A, John-sonEM (2001) Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron 29:615-628.
55. Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337-1349.
56. Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372-380.
57. Richter BW, Mir SS, Eiben LJ, Lewis J, Reffey SB, Frattini A, Tian L, Frank S, Youle RJ, Nelson DL, Notarangelo LD, Vezzoni P, Fearnhead HO, Duck-ett CS (2001) Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family. Mol Cell Biol 21:4292-4301.
58. Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55-66.
59. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR (1999a) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8:397-407.
60. Schilling G, Wood JD, Duan K, Slunt HH, Gonzales V, Yamada M, Cooper JK, Margolis RL, Jenkins NA, Copeland NG, Takahashi H, Tsuji S, Price DL, Borchelt DR, Ross CA (1999b) Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24:275-286.
61. SekineY,TakedaK, Ichijo H (2006) The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med 6:87-97.
62. Sherman MY, Goldberg AL (2001) Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29:15-32.
63. Shinoe T, Wanaka A, Nikaido T, Kanazawa K, Shimizu J, Imaizumi K, Ka-nazawa I (2001) Upregulation of the pro-apoptotic BH3-only peptide harakiri in spinal neurons of amyotrophic lateral sclerosis patients. Neu-rosci Lett 313:153-157.
64. Skinner PJ, Koshy BT, Cummings CJ, Klement IA, Helin K, Servadio A, Zoghbi HY, Orr HT (1997) Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389:971-974.
65. Sopher BL, Thomas PS Jr, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada AR (2004) Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41:687-699.
66. Sperandio S, de Belle I, Bredesen DE (2000) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 97:14376-14381.
67. Stennicke HR, Salvesen GS (1998) Properties of the caspases. Biochim Bio-phys Acta 1387:17-31.
68. Takeyama K, Ito S, Yamamoto A, Tanimoto H, Furutani T, Kanuka H, Miura M, Tabata T, Kato S (2002) Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35:855-864.
69. Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenera-tive disease. Science 296:1991-1995.
70. Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A, Markovic-Plese S, Fischbeck KH (2003) Aggresomes protect cells byenhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 12:749-757.
71. Turmaine M, Raza A, Mahal A, Mangiarini L, Bates GP, Davies SW (2000) Nonapoptotic neurodegeneration in a transgenic mouse model of Hun-tington's disease. Proc Natl Acad Sci USA 97:8093-8097.
72. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664-666.
73. Walcott JL, Merry DE (2002) Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J Biol Chem 277:50855-50859.
74. Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY, Huang PC, Li AH (2006) Polyglutamine-expanded ataxin-7 activates mitochondrial apo-ptotic pathway of cerebellar neurons by upregulating Bax and downregu-lating Bcl-x(L). Cell Signal 18:541-552.
75. Warby SC, Doty CN, Graham RK, Carroll JB, Yang YZ, Singaraja RR, Overall CM, Hayden MR (2008) Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet 17:2390-2404.
76. Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR (1998) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 273:9158-9167.
77. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J (2001) Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29:629-643.
78. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315:856-859.
79. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802-809.
80. Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217-247.