Skip to main content
SpringerLink
Log in
Book cover

Essentials of Apoptosis pp 479–504Cite as

Apoptosis in Neurodegenerative Diseases

  • Chapter
  • First Online:

Abstract

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are a group of age-dependent, progressive disorders that exhibit prominent neuronal death. Alzheimer’s disease and Parkinson’s disease are mainly sporadic, whereas Huntington’s disease is entirely genetic. Studies on human postmortem brains highlighted the possible involvement of apoptosis and autophagy in neuron death in the diseases. Studies using genetically engineered mouse models confirmed contributions of key apoptosis genes in disease progression in these experimental systems. In addition, mouse models confirmed that neurotoxins may accelerate and exacerbate disease progression. A better understanding of neuron death mechanisms in these diseases will help design better treatment strategies.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Lee VM, Trojanowski JQ. Progress from Alzheimer's tangles to pathological tau points towards more effective therapies now. J Alzheimer Dis 2006;9(3 Suppl):257–62.

    CAS  Google Scholar 

  2. Roberson ED, Mucke L. 100 years and counting: Prospects for defeating Alzheimer's disease. Science 2006;314(5800):781–4.

    Article  PubMed  CAS  Google Scholar 

  3. Lassmann H, Bancher C, Breitschopf H, et al. Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ. Acta Neuropathol 1995;89(1):35–41.

    Article  PubMed  CAS  Google Scholar 

  4. Drache B, Diehl GE, Beyreuther K, Perlmutter LS, Konig G. Bcl-xl-specific antibody labels activated microglia associated with Alzheimer's disease and other pathological states. J Neurosci Res 1997;47(1):98–108.

    Article  PubMed  CAS  Google Scholar 

  5. O'Barr S, Schultz J, Rogers J. Expression of the protooncogene bcl-2 in Alzheimer's disease brain. Neurobiol Aging 1996;17(1):131–6.

    Article  PubMed  Google Scholar 

  6. Nagy ZS, Esiri MM. Apoptosis-related protein expression in the hippocampus in Alzheimer's disease. Neurobiol Aging 1997;18(6):565–71.

    Article  PubMed  CAS  Google Scholar 

  7. MacGibbon GA, Lawlor PA, Sirimanne ES, et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997;750(1–2):223–34.

    Article  PubMed  CAS  Google Scholar 

  8. Kitamura Y, Shimohama S, Kamoshima W, et al. Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease. Brain Res 1998;780(2):260–9.

    Article  PubMed  CAS  Google Scholar 

  9. Su JH, Deng G, Cotman CW. Bax protein expression is increased in Alzheimer's brain: Correlations with DNA damage, Bcl-2 expression, and brain pathology. J Neuropathol Exp Neurol 1997;56(1):86–93.

    Article  PubMed  CAS  Google Scholar 

  10. Giannakopoulos P, Kovari E, Savioz A, et al. Differential distribution of presenilin-1, Bax, and Bcl-X(L) in Alzheimer's disease and frontotemporal dementia. Acta Neuropathol 1999;98(2):141–9.

    Article  PubMed  CAS  Google Scholar 

  11. Tortosa A, Lopez E, Ferrer I. Bcl-2 and Bax protein expression in Alzheimer's disease. Acta Neuropathol 1998;95(4):407–12.

    Article  PubMed  CAS  Google Scholar 

  12. Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LA. Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis. J Neurosci 2007;27(4):893–900.

    Article  PubMed  CAS  Google Scholar 

  13. Yang F, Sun X, Beech W, et al. Antibody to caspase-cleaved actin detects apoptosis in differentiated neuroblastoma and plaque-associated neurons and microglia in Alzheimer's disease. Am J Pathol 1998;152(2):379–89.

    PubMed  CAS  Google Scholar 

  14. Chan SL, Griffin WS, Mattson MP. Evidence for caspase-mediated cleavage of AMPA receptor subunits in neuronal apoptosis and Alzheimer's disease. J Neurosci Res 1999;57(3): 315–23.

    Article  PubMed  CAS  Google Scholar 

  15. Albrecht S, Bourdeau M, Bennett D, Mufson EJ, Bhattacharjee M, LeBlanc AC. Activation of caspase-6 in aging and mild cognitive impairment. Am J Pathol 2007;170(4):1200–9.

    Article  PubMed  CAS  Google Scholar 

  16. Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC. Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. Am J Pathol 2004;165(2):523–31.

    Article  PubMed  CAS  Google Scholar 

  17. 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 1999;274(33):23426–36.

    Article  PubMed  CAS  Google Scholar 

  18. Stadelmann C, Deckwerth TL, Srinivasan A, et al. 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 1999;155(5):1459–66.

    Article  CAS  Google Scholar 

  19. Uetsuki T, Takemoto K, Nishimura I, et al. Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein. J Neurosci 1999;19(16):6955–64.

    PubMed  CAS  Google Scholar 

  20. Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain. Neurobiol Dis 2002;11(2):341–54.

    Article  PubMed  CAS  Google Scholar 

  21. Rohn TT, Head E, Nesse WH, Cotman CW, Cribbs DH. Activation of caspase-8 in the Alzheimer's disease brain. Neurobiol Dis 2001;8(6):1006–16.

    Article  PubMed  CAS  Google Scholar 

  22. Pompl PN, Yemul S, Xiang Z, et al. Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch Neurol 2003;60(3):369–76.

    Article  PubMed  Google Scholar 

  23. Wu CK, Thal L, Pizzo D, Hansen L, Masliah E, Geula C. Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease. Exp Neurol 2005;195(2):484–96.

    Article  PubMed  CAS  Google Scholar 

  24. McGowan E, Eriksen J, Hutton M. A decade of modeling Alzheimer's disease in transgenic mice. Trends Genet 2006;22(5):281–9.

    Article  PubMed  CAS  Google Scholar 

  25. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet 1995;9(1):21–30.

    Article  PubMed  CAS  Google Scholar 

  26. Calhoun ME, Burgermeister P, Phinney AL, et al. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 1999;96(24):14088–93.

    Article  PubMed  CAS  Google Scholar 

  27. Calhoun ME, Wiederhold KH, Abramowski D, et al. Neuron loss in APP transgenic mice. Nature 1998;395(6704):755–6.

    Article  PubMed  CAS  Google Scholar 

  28. Sturchler-Pierrat C, Abramowski D, Duke M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997;94(24):13287–92.

    Article  PubMed  CAS  Google Scholar 

  29. Hauptmann S, Scherping I, Drose S, et al. Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 2008.

    Google Scholar 

  30. Hwang DY, Cho JS, Lee SH, et al. Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw. Exp Neurol 2004;186(1):20–32.

    Article  PubMed  CAS  Google Scholar 

  31. SantaCruz K, Lewis J, Spires T, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005;309(5733):476–81.

    Article  PubMed  CAS  Google Scholar 

  32. Zehr C, Lewis J, McGowan E, et al. Apoptosis in oligodendrocytes is associated with axonal degeneration in P301L tau mice. Neurobiol Dis 2004;15(3):553–62.

    Article  PubMed  CAS  Google Scholar 

  33. Lewis J, McGowan E, Rockwood J, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 2000;25(4):402–5.

    Article  PubMed  CAS  Google Scholar 

  34. Allen B, Ingram E, Takao M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 2002;22(21):9340–51.

    PubMed  CAS  Google Scholar 

  35. Zhang B, Higuchi M, Yoshiyama Y, et al. Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy. J Neurosci 2004;24(19):4657–67.

    Article  PubMed  CAS  Google Scholar 

  36. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 2005;25(22):5446–54.

    Article  PubMed  CAS  Google Scholar 

  37. Ramalho RM`, Viana RS, Castro RE, Steer CJ, Low WC, Rodrigues CM. Apoptosis in transgenic mice expressing the P301L mutated form of human tau. Mol Med 2008;14(5-6):309–17.

    Google Scholar 

  38. Ribe EM, Perez M, Puig B, et al. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 2005;20(3):814–22.

    Article  PubMed  CAS  Google Scholar 

  39. Schmitz C, Rutten BP, Pielen A, et al. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Am J Pathol 2004;164(4):1495–502.

    Article  PubMed  Google Scholar 

  40. Oakley H, Cole SL, Logan S, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation. J Neurosci 2006;26(40):10129–40.

    Article  PubMed  CAS  Google Scholar 

  41. Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromolecular Med 2003;4(1–2):21–36.

    Article  PubMed  CAS  Google Scholar 

  42. Hirai K, Aliev G, Nunomura A, et al. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 2001;21(9):3017–23.

    PubMed  CAS  Google Scholar 

  43. Kitamura Y, Taniguchi T, Shimohama S. Apoptotic cell death in neurons and glial cells: Implications for Alzheimer's disease. Jpn J Pharmacol 1999;79(1):1–5.

    Article  PubMed  CAS  Google Scholar 

  44. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 1997;17(8):2653–7.

    PubMed  CAS  Google Scholar 

  45. Good PF, Werner P, Hsu A, Olanow CW, Perl DP. Evidence of neuronal oxidative damage in Alzheimer's disease. Am J Pathol 1996;149(1):21–8.

    PubMed  CAS  Google Scholar 

  46. Aksenov MY, Tucker HM, Nair P, et al. The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer's disease. Neurochem Res 1999;24(6):767–74.

    Article  PubMed  CAS  Google Scholar 

  47. Aksenov MY, Tucker HM, Nair P, et al. The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease. J Mol Neurosci 1998;11(2):151–64.

    Article  PubMed  CAS  Google Scholar 

  48. Dyrks T, Dyrks E, Hartmann T, Masters C, Beyreuther K. Amyloidogenicity of beta A4 and beta A4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem 1992;267(25):18210–7.

    PubMed  CAS  Google Scholar 

  49. Li F, Calingasan NY, Yu F, et al. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 2004;89(5):1308–12.

    Article  PubMed  CAS  Google Scholar 

  50. Maurer I, Zierz S, Moller HJ. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging 2000;21(3):455–62.

    Article  PubMed  CAS  Google Scholar 

  51. Valla J, Berndt JD, Gonzalez-Lima F. Energy hypometabolism in posterior cingulate cortex of Alzheimer's patients: Superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 2001;21(13):4923–30.

    PubMed  CAS  Google Scholar 

  52. Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem 1994;63(6):2179–84.

    Article  PubMed  CAS  Google Scholar 

  53. Kish SJ, Mastrogiacomo F, Guttman M, et al. Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and in hereditary spinocerebellar ataxia disorders: A nonspecific change? J Neurochem 1999;72(2):700–7.

    Article  CAS  Google Scholar 

  54. Kish SJ, Bergeron C, Rajput A, et al. Brain cytochrome oxidase in Alzheimer's disease. J Neurochem 1992;59(2):776–9.

    Article  PubMed  CAS  Google Scholar 

  55. Bosetti F, Brizzi F, Barogi S, et al. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol Aging 2002;23(3):371–6.

    Article  PubMed  CAS  Google Scholar 

  56. Parker WD, Jr., Parks J, Filley CM, Kleinschmidt-DeMasters BK. Electron transport chain defects in Alzheimer's disease brain. Neurology 1994;44(6):1090–6.

    Article  PubMed  Google Scholar 

  57. Parker WD, Jr., Mahr NJ, Filley CM, et al. Reduced platelet cytochrome c oxidase activity in Alzheimer's disease. Neurology 1994;44(6):1086–90.

    Article  PubMed  Google Scholar 

  58. Parker WD, Jr., Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology 1990;40(8):1302–3.

    Article  PubMed  Google Scholar 

  59. Canevari L, Clark JB, Bates TE. Beta-amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 1999;457(1):131–4.

    Article  PubMed  CAS  Google Scholar 

  60. Eckert A, Hauptmann S, Scherping I, et al. Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice. Neurodegener Dis 2008;5(3–4):157–9.

    Article  PubMed  CAS  Google Scholar 

  61. Keil U, Bonert A, Marques CA, et al. Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 2004;279(48):50310–20.

    Article  PubMed  CAS  Google Scholar 

  62. Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 2003;161(1):41–54.

    Article  PubMed  CAS  Google Scholar 

  63. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 2006;15(9):1437–49.

    Article  PubMed  CAS  Google Scholar 

  64. Takuma H, Tomiyama T, Kuida K, Mori H. Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo. J Neuropathol Exp Neurol 2004;63(3):255–61.

    PubMed  CAS  Google Scholar 

  65. Cozzolino M, Ferraro E, Ferri A, et al. Apoptosome inactivation rescues proneural and neural cells from neurodegeneration. Cell Death Differ 2004;11(11):1179–91.

    Article  PubMed  CAS  Google Scholar 

  66. Troy CM, Rabacchi SA, Friedman WJ, Frappier TF, Brown K, Shelanski ML. Caspase-2 mediates neuronal cell death induced by beta-amyloid. J Neurosci 2000;20(4):1386–92.

    PubMed  CAS  Google Scholar 

  67. Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie LA, Head E. Lack of pathology in a triple transgenic mouse model of Alzheimer's disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci 2008;28(12):3051–9.

    Article  PubMed  CAS  Google Scholar 

  68. He P, Zhong Z, Lindholm K, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol 2007;178(5):829–41.

    Article  PubMed  CAS  Google Scholar 

  69. Syntichaki P, Tavernarakis N. The biochemistry of neuronal necrosis: Rogue biology? Nat Rev Neurosci 2003;4(8):672–84.

    Article  CAS  Google Scholar 

  70. Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 2007;120(Pt 23):4081–91.

    Article  PubMed  CAS  Google Scholar 

  71. Massey AC, Zhang C, Cuervo AM. Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 2006;73:205–35.

    Article  PubMed  CAS  Google Scholar 

  72. Khachaturian ZS. Hypothesis on the regulation of cytosol calcium concentration and the aging brain. Neurobiol Aging 1987;8(4):345–6.

    Article  PubMed  CAS  Google Scholar 

  73. Lopez JR, Lyckman A, Oddo S, LaFerla FM, Querfurth HW, Shtifman A, Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. J Neurochem 2008;105(1):262–71.

    Article  PubMed  CAS  Google Scholar 

  74. Stutzmann GE, Caccamo A, LaFerla FM, Parker I. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer's-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 2004;24(2):508–13.

    Article  PubMed  CAS  Google Scholar 

  75. Simakova O, Arispe NJ. Early and late cytotoxic effects of external application of the Alzheimer's Abeta result from the initial formation and function of Abeta ion channels. Biochemistry 2006;45(18):5907–15.

    Article  PubMed  CAS  Google Scholar 

  76. Thibault O, Gant JC, Landfield PW. Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: Minding the store. Aging Cell 2007;6(3):307–17.

    Article  PubMed  CAS  Google Scholar 

  77. Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2007;4(2).

    Google Scholar 

  78. Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA. Properties of the endosomal-lysosomal system in the human central nervous system: Disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci 1996;16(1):186–99.

    PubMed  CAS  Google Scholar 

  79. Yu WH, Kumar A, Peterhoff C, et al. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: Implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol 2004;36(12):2531–40.

    Article  PubMed  CAS  Google Scholar 

  80. Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 1994;369(6480):488–91.

    Article  PubMed  CAS  Google Scholar 

  81. Zheng H, Jiang M, Trumbauer ME, et al. Mice deficient for the amyloid precursor protein gene. Ann NY Acad Sci 1996;777:421–6.

    Article  PubMed  CAS  Google Scholar 

  82. Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003;40(6):1087–93.

    Article  PubMed  CAS  Google Scholar 

  83. Marr RA, Rockenstein E, Mukherjee A, et al. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 2003;23(6):1992–6.

    PubMed  CAS  Google Scholar 

  84. Choi DS, Wang D, Yu GQ, et al. PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc Natl Acad Sci USA 2006;103(21):8215–20.

    Article  PubMed  CAS  Google Scholar 

  85. Mueller-Steiner S, Zhou Y, Arai H, et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: Implications for Alzheimer's disease. Neuron 2006;51(6):703–14.

    Article  PubMed  CAS  Google Scholar 

  86. Imbimbo BP. Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem 2008;8(1):54–61.

    Article  PubMed  CAS  Google Scholar 

  87. Olson RE, Albright CF. Recent progress in the medicinal chemistry of gamma-secretase inhibitors. Curr Top Med Chem 2008;8(1):17–33.

    Article  PubMed  CAS  Google Scholar 

  88. Wolfe MS. Gamma-secretase inhibition and modulation for Alzheimer's disease. Curr Alzheimer Res 2008;5(2):158–64.

    Article  PubMed  CAS  Google Scholar 

  89. Zhao B, Yu M, Neitzel M, et al. Identification of gamma-secretase inhibitor potency determinants on presenilin. J Biol Chem 2008;283(5):2927–38.

    Article  PubMed  CAS  Google Scholar 

  90. Chen G, Chen KS, Kobayashi D, et al. Active beta-amyloid immunization restores spatial learning in PDAPP mice displaying very low levels of beta-amyloid. J Neurosci 2007;27(10):2654–62.

    Article  PubMed  CAS  Google Scholar 

  91. Patton RL, Kalback WM, Esh CL, et al. Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: A biochemical analysis. Am J Pathol 2006;169(3):1048–63.

    Article  PubMed  CAS  Google Scholar 

  92. Lee VM, Trojanowski JQ. Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: New targets for drug discovery. Neuron 2006;52(1):33–8.

    Article  PubMed  CAS  Google Scholar 

  93. Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: Molecules to medicine. J Clin Invest 2006;116(7):1744–54.

    Article  PubMed  CAS  Google Scholar 

  94. Morris HR. Genetics of Parkinson's disease. Ann Med 2005;37(2):86–96.

    Article  PubMed  CAS  Google Scholar 

  95. Cookson MR. The biochemistry of Parkinson's disease. Annu Rev Biochem 2005;74:29–52.

    Article  PubMed  CAS  Google Scholar 

  96. Lim KL, Chew KC, Tan JM, et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: Implications for Lewy body formation. J Neurosci 2005;25(8):2002–9.

    Article  PubMed  CAS  Google Scholar 

  97. Chung KK, Zhang Y, Lim KL, et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: Implications for Lewy-body formation in Parkinson disease. Nat Med 2001;7(10):1144–50.

    Article  PubMed  CAS  Google Scholar 

  98. Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM. Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies. Am J Pathol 2003;163(1):91–100.

    Article  PubMed  CAS  Google Scholar 

  99. Chu CT, Caruso JL, Cummings TJ, Ervin J, Rosenberg C, Hulette CM. Ubiquitin immunochemistry as a diagnostic aid for community pathologists evaluating patients who have dementia. Mod Pathol 2000;13(4):420–6.

    Article  PubMed  CAS  Google Scholar 

  100. Chen L, Thiruchelvam MJ, Madura K, Richfield EK. Proteasome dysfunction in aged human alpha-synuclein transgenic mice. Neurobiol Dis 2006;23(1):120–6.

    Article  PubMed  CAS  Google Scholar 

  101. Hashimoto M, Rockenstein E, Masliah E. Transgenic models of alpha-synuclein pathology: Past, present, and future. Ann NY Acad Sci 2003;991:171–88.

    Article  PubMed  CAS  Google Scholar 

  102. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002;34(4):521–33.

    Article  PubMed  CAS  Google Scholar 

  103. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 2000;287(5456):1265–9.

    Article  PubMed  CAS  Google Scholar 

  104. Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 2006;313(5785):324–8.

    Article  PubMed  CAS  Google Scholar 

  105. Cao S, Gelwix CC, Caldwell KA, Caldwell GA. Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J Neurosci 2005;25(15):3801–12.

    Article  PubMed  CAS  Google Scholar 

  106. Lakso M, Vartiainen S, Moilanen AM, et al. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 2003;86(1):165–72.

    Article  PubMed  CAS  Google Scholar 

  107. Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ. Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 2003;302(5651):1769–72.

    Article  PubMed  CAS  Google Scholar 

  108. Whitworth AJ, Wes PD, Pallanck LJ. Drosophila models pioneer a new approach to drug discovery for Parkinson's disease. Drug Discov Today 2006;11(3–4):119–26.

    Article  PubMed  CAS  Google Scholar 

  109. Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL. Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 2004;25(5):761–9.

    Article  PubMed  CAS  Google Scholar 

  110. Robertson DC, Schmidt O, Ninkina N, Jones PA, Sharkey J, Buchman VL. Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice. J Neurochem 2004;89(5):1126–36.

    Article  PubMed  CAS  Google Scholar 

  111. Dauer W, Kholodilov N, Vila M, et al. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 2002;99(22):14524–9.

    Article  PubMed  CAS  Google Scholar 

  112. Fountaine TM, Wade-Martins R. RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. J Neurosci Res 2007;85(2):351–63.

    Article  PubMed  CAS  Google Scholar 

  113. Hayashita-Kinoh H, Yamada M, Yokota T, Mizuno Y, Mochizuki H. Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson's disease rat model. Biochem Biophys Res Commun 2006;341(4):1088–95.

    Article  PubMed  CAS  Google Scholar 

  114. Gasser T. Genetics of Parkinson's disease. Curr Opin Neurol 2005;18(4):363–9.

    Article  PubMed  CAS  Google Scholar 

  115. Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet 2007;16 Spec No. 2:R183–R194.

    Article  CAS  Google Scholar 

  116. Giasson BI, Van DV. Mutations in LRRK2 as a cause of Parkinson's disease. Neurosignals 2008;16(1):99–105.

    Article  PubMed  CAS  Google Scholar 

  117. Zimprich A, Biskup S, Leitner P. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44(4):601–7.

    Article  PubMed  CAS  Google Scholar 

  118. Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44(4):595–600.

    Article  PubMed  CAS  Google Scholar 

  119. Shin N, Jeong H, Kwon J, et al., LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 2008;314(10):2055–65.

    Google Scholar 

  120. West AB, Moore DJ, Choi C, et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 2007;16(2):223–32.

    Article  PubMed  CAS  Google Scholar 

  121. Greggio E, Jain S, Kingsbury A, et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 2006;23(2):329–41.

    Article  PubMed  CAS  Google Scholar 

  122. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 2006;9(10):1231–3.

    Article  PubMed  CAS  Google Scholar 

  123. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392(6676):605–8.

    Article  PubMed  CAS  Google Scholar 

  124. Anderson LR, Betarbet R, Gearing M, et al. PARK10 candidate RNF11 is expressed by vulnerable neurons and localizes to Lewy bodies in Parkinson disease brain. J Neuropathol Exp Neurol 2007;66(10):955–64.

    Article  PubMed  CAS  Google Scholar 

  125. Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006;38(10):1184–91.

    Article  PubMed  CAS  Google Scholar 

  126. Valente EM, bou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;304(5674):1158–60.

    Article  PubMed  CAS  Google Scholar 

  127. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299(5604):256–9.

    Article  PubMed  CAS  Google Scholar 

  128. Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 2005;14(15):2099–111.

    Article  PubMed  CAS  Google Scholar 

  129. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol 1997;12(1):25–31.

    PubMed  CAS  Google Scholar 

  130. Anglade P, Vyas S, Hirsch EC, Agid Y. Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol Histopathol 1997;12(3):603–10.

    PubMed  CAS  Google Scholar 

  131. Mochizuki H, Goto K, Mori H, Mizuno Y. Histochemical detection of apoptosis in Parkinson's disease. J Neurol Sci 1996;137(2):120–3.

    Article  PubMed  CAS  Google Scholar 

  132. Tatton NA, lean-Fraser A, Tatton WG, Perl DP, Olanow CW. A fluorescent double-labeling method to detect and confirm apoptotic nuclei in Parkinson's disease. Ann Neurol 1998;44(3 Suppl 1):S142–8.

    PubMed  CAS  Google Scholar 

  133. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov Disord 1998;13(2):221–7.

    Article  PubMed  CAS  Google Scholar 

  134. Hartmann A, Hunot S, Michel PP, et al. Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease. Proc Natl Acad Sci USA 2000;97(6):2875–80.

    Article  PubMed  CAS  Google Scholar 

  135. Hartmann A, Mouatt-Prigent A, Vila M, et al. Increased expression and redistribution of the antiapoptotic molecule Bcl-xL in Parkinson's disease. Neurobiol Dis 2002;10(1):28–32.

    Article  PubMed  CAS  Google Scholar 

  136. Hartmann A, Mouatt-Prigent A, Faucheux BA, Agid Y, Hirsch EC. FADD: A link between TNF family receptors and caspases in Parkinson's disease. Neurology 2002;58(2):308–10.

    Article  PubMed  CAS  Google Scholar 

  137. Hartmann A, Michel PP, Troadec JD, et al. Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease? J Neurochem 2001;76(6):1785–93.

    Article  PubMed  CAS  Google Scholar 

  138. Vyas S, Javoy-Agid F, Herrero MT, et al. Expression of Bcl-2 in adult human brain regions with special reference to neurodegenerative disorders. J Neurochem 1997;69(1):223–31.

    Article  PubMed  CAS  Google Scholar 

  139. Hartmann A, Troadec JD, Hunot S, et al. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J Neurosci 2001;21(7):2247–55.

    PubMed  CAS  Google Scholar 

  140. Langston JW, Langston EB, Irwin I. MPTP-induced parkinsonism in human and non-human primates—Clinical and experimental aspects. Acta Neurol Scand Suppl 1984;100:49–54.

    PubMed  CAS  Google Scholar 

  141. Przedborski S, Jackson-Lewis V, Naini AB, et al. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): A technical review of its utility and safety. J Neurochem 2001;76(5):1265–74.

    Article  PubMed  CAS  Google Scholar 

  142. Maingay M, Romero-Ramos M, Kirik D. Viral vector mediated overexpression of human alpha-synuclein in the nigrostriatal dopaminergic neurons: A new model for Parkinson's disease. CNS Spectr 2005;10(3):235–44.

    PubMed  Google Scholar 

  143. Bove J, Prou D, Perier C, Przedborski S. Toxin-induced models of Parkinson's disease. NeuroRx 2005;2(3):484–94.

    Article  PubMed  Google Scholar 

  144. Jonsson G. Studies on the mechanisms of 6-hydroxydopamine cytotoxicity. Med Biol 1976;54(6):406–20.

    PubMed  CAS  Google Scholar 

  145. Young RC, Ervin GN, Smith GP. Abnormal open field behavior after anterolateral hypothalamic injection of 6-hydroxydopamine. Pharmacol Biochem Behav 1976;5(5):565–70.

    Article  PubMed  CAS  Google Scholar 

  146. Butcher LL. Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine. J Neural Transm 1975;37(3):189–203.

    Article  PubMed  CAS  Google Scholar 

  147. Saner A, Thoenen H. Model experiments on the molecular mechanism of action of 6-hydroxydopamine. Mol Pharmacol 1971;7(2):147–54.

    PubMed  CAS  Google Scholar 

  148. Heikkila R, Cohen G. Inhibition of biogenic amine uptake by hydrogen peroxide: A mechanism for toxic effects of 6-hydroxydopamine. Science 1971;172(989):1257–8.

    Article  PubMed  CAS  Google Scholar 

  149. Glinka Y, Gassen M, Youdim MB. Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm Suppl 1997;50:55–66.

    Article  PubMed  CAS  Google Scholar 

  150. Glinka Y, Tipton KF, Youdim MB. Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. J Neurochem 1996;66(5):2004–10.

    Article  PubMed  CAS  Google Scholar 

  151. Zuch CL, Nordstroem VK, Briedrick LA, Hoernig GR, Granholm AC, Bickford PC. Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol 2000;427(3):440–54.

    Article  PubMed  CAS  Google Scholar 

  152. He Y, Lee T, Leong SK. 6-Hydroxydopamine induced apoptosis of dopaminergic cells in the rat substantia nigra. Brain Res 2000;858(1):163–6.

    Article  PubMed  CAS  Google Scholar 

  153. Choi WS, Yoon SY, Oh TH, Choi EJ, O'Malley KL, Oh YJ. Two distinct mechanisms are involved in 6-hydroxydopamine- and MPP+-induced dopaminergic neuronal cell death: Role of caspases, ROS, and JNK. J Neurosci Res 1999;57(1):86–94.

    Article  PubMed  CAS  Google Scholar 

  154. Oh JH, Choi WS, Kim JE, Seo JW, O'Malley KL, Oh YJ. Overexpression of HA-Bax but not Bcl-2 or Bcl-XL attenuates 6-hydroxydopamine-induced neuronal apoptosis. Exp Neurol 1998;154(1):193–8.

    Article  PubMed  CAS  Google Scholar 

  155. Jeon BS, Jackson-Lewis V, Burke RE. 6-Hydroxydopamine lesion of the rat substantia nigra: Time course and morphology of cell death. Neurodegeneration 1995;4(2):131–7.

    Article  PubMed  CAS  Google Scholar 

  156. Dawson TM, Dawson VL, Gage FH, Fisher LJ, Hunt MA, Wamsley JK. Downregulation of muscarinic receptors in the rat caudate-putamen after lesioning of the ipsilateral nigrostriatal dopamine pathway with 6-hydroxydopamine (6-OHDA): Normalization by fetal mesencephalic transplants. Brain Res 1991;540(1–2):145–52.

    Article  PubMed  CAS  Google Scholar 

  157. Javoy F, Sotelo C, Herbet A, Agid Y. Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system. Brain Res 1976;102(2):201–15.

    Article  PubMed  CAS  Google Scholar 

  158. Agid Y, Javoy F, Glowinski J, Bouvet D, Sotelo C. Injection of 6-hydroxydopamine into the substantia nigra of the rat. II. Diffusion and specificity. Brain Res 1973;58(2):291–301.

    Article  CAS  Google Scholar 

  159. Sotelo C, Javoy F, Agid Y, Glowinski J. Injection of 6-hydroxydopamine in the substantia nigra of the rat. I. Morphological study. Brain Res 1973;58(2):269–90.

    Article  CAS  Google Scholar 

  160. Sherer TB, Betarbet R, Testa CM, et al. Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci 2003;23(34):10756–64.

    PubMed  CAS  Google Scholar 

  161. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000;3(12):1301–6.

    Article  PubMed  CAS  Google Scholar 

  162. Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW. Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci 2005;88(1):193–201.

    Article  PubMed  CAS  Google Scholar 

  163. Fei Q, Ethell DW. Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members. J Neurochem 2008;105:2091–2097.

    Google Scholar 

  164. Wang C, Ko HS, Thomas B, et al. Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. Hum Mol Genet 2005;14(24):3885–97.

    Article  PubMed  CAS  Google Scholar 

  165. Shimoda-Matsubayashi S, Hattori T, Matsumine H, et al. Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson's disease and control. Neurology 1997;49(5):1257–62.

    Article  PubMed  CAS  Google Scholar 

  166. Sian J, Dexter DT, Lees AJ, et al. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 1994;36(3):348–55.

    Article  PubMed  CAS  Google Scholar 

  167. Dexter DT, Carter CJ, Wells FR, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 1989;52(2):381–9.

    Article  PubMed  CAS  Google Scholar 

  168. Zhang J, Perry G, Smith MA, et al. Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol 1999;154(5):1423–9.

    Article  PubMed  CAS  Google Scholar 

  169. Dykens JA. Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: Implications for neurodegeneration. J Neurochem 1994;63(2):584–91.

    Article  PubMed  CAS  Google Scholar 

  170. Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006;38(5):515–7.

    Article  PubMed  CAS  Google Scholar 

  171. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 2006;38(5):518–20.

    Article  PubMed  CAS  Google Scholar 

  172. Smigrodzki R, Parks J, Parker WD. High frequency of mitochondrial complex I mutations in Parkinson's disease and aging. Neurobiol Aging 2004;25(10):1273–81.

    Article  PubMed  CAS  Google Scholar 

  173. Simon DK, Lin MT, Zheng L, et al. Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease. Neurobiol Aging 2004;25(1):71–81.

    Article  PubMed  CAS  Google Scholar 

  174. Schapira AH, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson's disease. J Neurochem 1990;55(6):2142–5.

    Article  PubMed  CAS  Google Scholar 

  175. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 1990;54(3):823–7.

    Article  PubMed  CAS  Google Scholar 

  176. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1989;1(8649):1269.

    Article  PubMed  CAS  Google Scholar 

  177. Hassouna I, Wickert H, Zimmermann M, Gillardon F. Increase in bax expression in substantia nigra following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment of mice. Neurosci Lett 1996;204(1–2):85–8.

    Article  PubMed  CAS  Google Scholar 

  178. Novikova L, Garris BL, Garris DR, Lau YS. Early signs of neuronal apoptosis in the substantia nigra pars compacta of the progressive neurodegenerative mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid model of Parkinson's disease. Neuroscience 2006;140(1):67–76.

    Article  PubMed  CAS  Google Scholar 

  179. Turmel H, Hartmann A, Parain K, et al. Caspase-3 activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Mov Disord 2001;16(2):185–9.

    Article  PubMed  CAS  Google Scholar 

  180. Hanrott K, Gudmunsen L, O'Neill MJ, Wonnacott S. 6-Hydroxydopamine-induced apoptosis is mediated via extracellular auto-oxidation and caspase 3-dependent activation of protein kinase Cdelta. J Biol Chem 2006;281(9):5373–82.

    Article  PubMed  CAS  Google Scholar 

  181. Vila M, Jackson-Lewis V, Vukosavic S, et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Proc Natl Acad Sci USA 2001;98(5):2837–42.

    Article  PubMed  CAS  Google Scholar 

  182. Perier C, Bove J, Wu DC, et al. Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease. Proc Natl Acad Sci USA 2007;104(19):8161–6.

    Article  PubMed  CAS  Google Scholar 

  183. Furuya T, Hayakawa H, Yamada M, et al. Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. J Neurosci 2004;24(8):1865–72.

    Article  PubMed  CAS  Google Scholar 

  184. Rousselet E, Callebert J, Parain K, et al. Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP. Exp Neurol 2002;177(1):183–92.

    Article  PubMed  CAS  Google Scholar 

  185. Yang L, Matthews RT, Schulz JB, et al. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2. J Neurosci 1998;18(20):8145–52.

    PubMed  CAS  Google Scholar 

  186. Offen D, Beart PM, Cheung NS, et al. Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Proc Natl Acad Sci USA 1998;95(10):5789–94.

    Article  PubMed  CAS  Google Scholar 

  187. Cleren C, Yang L, Lorenzo B, et al. Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of parkinsonism. J Neurochem 2008;104(6):1613–21.

    Article  PubMed  CAS  Google Scholar 

  188. Rosenblad C, Kirik D, Devaux B, Moffat B, Phillips HS, Bjorklund A. Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle. Eur J Neurosci 1999;11(5):1554–66.

    Article  PubMed  CAS  Google Scholar 

  189. Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000;290(5492):767–73.

    Article  PubMed  CAS  Google Scholar 

  190. Cuervo AM, Dice JF. Age-related decline in chaperone-mediated autophagy. J Biol Chem 2000;275(40):31505–13.

    Article  PubMed  CAS  Google Scholar 

  191. Kiffin R, Kaushik S, Zeng M, et al. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci 2007;120(Pt 5):782–91.

    Article  PubMed  CAS  Google Scholar 

  192. Cuervo AM, Dice JF. When lysosomes get old. Exp Gerontol 2000;35(2):119–31.

    Article  PubMed  CAS  Google Scholar 

  193. Lavrov AY, Ilyna ES, Zakharova EY, Boukina AM, Tishkanina SV. The first three Russian cases of classical, late-infantile, neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol 2002;6(3):161–4.

    Article  PubMed  Google Scholar 

  194. Nijssen PC, Brusse E, Leyten AC, Martin JJ, Teepen JL, Roos RA. Autosomal dominant adult neuronal ceroid lipofuscinosis: Parkinsonism due to both striatal and nigral dysfunction. Mov Disord 2002;17(3):482–7.

    Article  PubMed  Google Scholar 

  195. Zimran A, Neudorfer O, Elstein D. The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2005;352(7):728–31.

    Article  PubMed  Google Scholar 

  196. Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82(3):192–207.

    Article  PubMed  CAS  Google Scholar 

  197. Saito Y, Suzuki K, Hulette CM, Murayama S. Aberrant phosphorylation of alpha-synuclein in human Niemann-Pick type C1 disease. J Neuropathol Exp Neurol 2004;63(4):323–8.

    PubMed  CAS  Google Scholar 

  198. Suzuki K, Iseki E, Togo T, et al. Neuronal and glial accumulation of alpha- and beta-synucleins in human lipidoses. Acta Neuropathol (Berl) 2007;114(5):481–9.

    Article  CAS  Google Scholar 

  199. Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005;169(3):425–34.

    Article  PubMed  CAS  Google Scholar 

  200. Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441:885–9.

    Article  PubMed  CAS  Google Scholar 

  201. Klockgether T, Turski L. NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats. Ann Neurol 1990;28(4):539–46.

    Article  PubMed  CAS  Google Scholar 

  202. Myrianthopoulos NC. Huntington's chorea. J Med Genet 1966;3(4):298–314.

    Article  PubMed  CAS  Google Scholar 

  203. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP, Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 1985;44(6):559–77.

    Article  PubMed  CAS  Google Scholar 

  204. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotiderepeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72(6):971–83.

    Google Scholar 

  205. Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997;60(5):1202–10.

    PubMed  CAS  Google Scholar 

  206. Penney JB, Jr., Vonsattel JP, MacDonald ME, Gusella JF, Myers RH. CAG repeat number governs the development rate of pathology in Huntington's disease. Ann Neurol 1997;41(5):689–92.

    Article  PubMed  Google Scholar 

  207. Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. Neurology 1999;52(2):392–4.

    Article  PubMed  CAS  Google Scholar 

  208. Nance MA. “U.S. Huntington Disease Genetic Testing Group”. Genetic testing of children at risk for Huntington's disease. Neurology 1997;49(4):1048–53.

    CAS  Google Scholar 

  209. Gutekunst CA, Levey AI, Heilman CJ, et al. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci USA 1995;92(19):8710–4.

    Article  PubMed  CAS  Google Scholar 

  210. Sharp AH, Loev SJ, Schilling G, et al. Widespread expression of Huntington's disease gene (IT15) protein product. Neuron 1995;14(5):1065–74.

    Article  PubMed  CAS  Google Scholar 

  211. Graveland GA, Williams RS, DiFiglia M. Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science 1985;227(4688):770–3.

    Article  PubMed  CAS  Google Scholar 

  212. Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE. Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 1995;15(5 Pt 2):3775–87.

    PubMed  CAS  Google Scholar 

  213. Thomas LB, Gates DJ, Richfield EK, O'Brien TF, Schweitzer JB, Steindler DA. DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions. Exp Neurol 1995;133(2):265–72.

    Article  PubMed  CAS  Google Scholar 

  214. Dragunow M, Faull RL, Lawlor P, et al. In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Neuroreport 1995;6(7):1053–7.

    Article  PubMed  CAS  Google Scholar 

  215. Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RL, Dragunow M. Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum. Neuroscience 1998;87(1):49–53.

    Article  PubMed  CAS  Google Scholar 

  216. Kiechle T, Dedeoglu A, Kubilus J, et al. Cytochrome C and caspase-9 expression in Huntington's disease. Neuromol Med 2002;1(3):183–95.

    Article  CAS  Google Scholar 

  217. Ona VO, Li M, Vonsattel JP, et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 1999;399(6733):263–7.

    Article  PubMed  CAS  Google Scholar 

  218. Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 1999;22(3):623–33.

    Article  PubMed  CAS  Google Scholar 

  219. Vis JC, Schipper E, de Boer-van Huizen RT, et al. Expression pattern of apoptosis-related markers in Huntington's disease. Acta Neuropathol 2005;109(3):321–8.

    Google Scholar 

  220. Hermel E, Gafni J, Propp SS, et al. Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death Differ 2004;11(4):424–38.

    Article  PubMed  CAS  Google Scholar 

  221. Goffredo D, Rigamonti D, Zuccato C, Tartari M, Valenza M, Cattaneo E. Prevention of cytosolic IAPs degradation: A potential pharmacological target in Huntington's disease. Pharmacol Res 2005;52(2):140–50.

    Article  PubMed  CAS  Google Scholar 

  222. Rubinsztein DC. Lessons from animal models of Huntington's disease. Trends Genet 2002;18(4):202–9.

    Article  PubMed  CAS  Google Scholar 

  223. Gu X, Li C, Wei W, et al. Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice. Neuron 2005;46(3):433–44.

    Article  PubMed  CAS  Google Scholar 

  224. Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996;87(3):493–506.

    Article  PubMed  CAS  Google Scholar 

  225. Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000;6(7):797–801.

    Article  PubMed  CAS  Google Scholar 

  226. Reddy PH, Williams M, Charles V, et al. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 1998;20(2):198–202.

    Article  PubMed  CAS  Google Scholar 

  227. Garcia-Martinez JM, Perez-Navarro E, Xifro X, et al. BH3-only proteins Bid and Bim(EL) are differentially involved in neuronal dysfunction in mouse models of Huntington's disease. J Neurosci Res 2007;85(12):2756–69.

    Article  PubMed  CAS  Google Scholar 

  228. Imarisio S, Carmichael J, Korolchuk V, et al. Huntington's disease: From pathology and genetics to potential therapies. Biochem J 2008;412(2):191–209.

    Article  PubMed  CAS  Google Scholar 

  229. Li XJ, Sharp AH, Li SH, Dawson TM, Snyder SH, Ross CA. Huntingtin-associated protein (HAP1): Discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase. Proc Natl Acad Sci USA 1996;93(10):4839–44.

    Article  PubMed  CAS  Google Scholar 

  230. Kaltenbach LS, Romero E, Becklin RR, et al. Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet 2007;3(5):e82.

    Article  PubMed  CAS  Google Scholar 

  231. Zhang Y, Ona VO, Li M, et al. Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington's disease. J Neurochem 2003;87(5):1184–92.

    Article  PubMed  CAS  Google Scholar 

  232. Wang X, Zhu S, Drozda M, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Proc Natl Acad Sci USA 2003;100(18):10483–7.

    Article  PubMed  CAS  Google Scholar 

  233. Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP. Neuroprotection in Huntington's disease: A 2-year study on minocycline. Int Clin Psychopharmacol 2004;19(6):337–42.

    Article  PubMed  Google Scholar 

  234. Turmaine M, Raza A, Mahal A, Mangiarini L, Bates GP, Davies SW. Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. Proc Natl Acad Sci USA 2000;97(14):8093–7.

    Article  PubMed  CAS  Google Scholar 

  235. DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;277(5334):1990–3.

    Article  PubMed  CAS  Google Scholar 

  236. Gafni J, Ellerby LM. Calpain activation in Huntington's disease. J Neurosci 2002;22(12):4842–9.

    PubMed  CAS  Google Scholar 

  237. Kim YJ, Yi Y, Sapp E, et al. Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci USA 2001;98(22):12784–9.

    Article  PubMed  CAS  Google Scholar 

  238. Mende-Mueller LM, Toneff T, Hwang SR, Chesselet MF, Hook VY. Tissue-specific proteolysis of huntingtin (htt) in human brain: Evidence of enhanced levels of N- and C-terminal htt fragments in Huntington's disease striatum. J Neurosci 2001;21(6):1830–7.

    PubMed  CAS  Google Scholar 

  239. Yu ZX, Li SH, Evans J, Pillarisetti A, Li H, Li XJ. Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington's disease. J Neurosci 2003;23(6):2193–202.

    PubMed  CAS  Google Scholar 

  240. Young AB, Greenamyre JT, Hollingsworth Z, et al. NMDA receptor losses in putamen from patients with Huntington's disease. Science 1988;241(4868):981–3.

    Article  PubMed  CAS  Google Scholar 

  241. Zeron MM, Fernandes HB, Krebs C, et al. Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease. Mol Cell Neurosci 2004;25(3):469–79.

    Article  PubMed  CAS  Google Scholar 

  242. Zeron MM, Hansson O, Chen N, et al. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 2002;33(6):849–60.

    Article  PubMed  CAS  Google Scholar 

  243. Zeron MM, Chen N, Moshaver A, et al. Mutant huntingtin enhances excitotoxic cell death. Mol Cell Neurosci 2001;17(1):41–53.

    Article  PubMed  CAS  Google Scholar 

  244. Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 2005;171(6):1001–12.

    Article  PubMed  CAS  Google Scholar 

  245. McGeer PL, McGeer EG. Intracerebral injections of kainic acid and tetanus toxin: Possible models for the signs of chorea and dystonia. Adv Neurol 1978;21:331–8.

    PubMed  CAS  Google Scholar 

  246. Coyle JT, Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 1976;263(5574):244–6.

    Article  PubMed  CAS  Google Scholar 

  247. Bordelon YM, Chesselet MF. Early effects of intrastriatal injections of quinolinic acid on microtubule-associated protein-2 and neuropeptides in rat basal ganglia. Neuroscience 1999;93(3):843–53.

    Article  PubMed  CAS  Google Scholar 

  248. Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci 1999;19(10):4023–33.

    PubMed  CAS  Google Scholar 

  249. Vis JC, Verbeek MM, de Waal RM, ten Donkelaar HJ, Kremer B. The mitochondrial toxin 3-nitropropionic acid induces differential expression patterns of apoptosis-related markers in rat striatum. Neuropathol Appl Neurobiol 2001;27(1):68–76.

    Article  PubMed  CAS  Google Scholar 

  250. Toulmond S, Tang K, Bureau Y, et al. Neuroprotective effects of M826, a reversible caspase-3 inhibitor, in the rat malonate model of Huntington's disease. Br J Pharmacol 2004;141(4):689–97.

    Article  PubMed  CAS  Google Scholar 

  251. Schiefer J, Landwehrmeyer GB, Luesse HG, et al. Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease. Mov Disord 2002;17(4):748–57.

    Article  PubMed  Google Scholar 

  252. Ferrante RJ, Kubilus JK, Lee J, et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci 2003;23(28):9418–27.

    PubMed  CAS  Google Scholar 

  253. O'Suilleabhain P, Dewey RB, Jr. A randomized trial of amantadine in Huntington disease. Arch Neurol 2003;60(7):996–8.

    Article  PubMed  Google Scholar 

  254. Dosage effects of riluzolein Huntington's disease: A multicenter placebo-controlled study. Neurology Huntington Study Group 2003;61(11):1551–6.

    Google Scholar 

  255. Kremer B, Clark CM, Almqvist EW, et al. Influence of lamotrigine on progression of early Huntington disease: A randomized clinical trial. Neurology Huntington Study Group 1999;53(5):1000–11.

    Article  PubMed  CAS  Google Scholar 

  256. A randomized, placebo-controlledtrial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 2001;57(3):397–404.

    Google Scholar 

  257. Mittoux V, Joseph JM, Conde F, et al. Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's disease. Hum Gene Ther 2000;11(8):1177–87.

    Article  PubMed  CAS  Google Scholar 

  258. Bloch J, Bachoud-Levi AC, Deglon N, et al. Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: Results of a phase I study. Hum Gene Ther 2004;15(10):968–75.

    Article  PubMed  CAS  Google Scholar 

  259. Wang YL, Liu W, Wada E, Murata M, Wada K, Kanazawa I. Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA. Neurosci Res 2005;53(3):241–9.

    Article  PubMed  CAS  Google Scholar 

  260. Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK, Hartl FU. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci USA 2000;97(14):7841–6.

    Article  PubMed  CAS  Google Scholar 

  261. Sittler A, Lurz R, Lueder G, et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum Mol Genet 2001;10(12):1307–15.

    Article  PubMed  CAS  Google Scholar 

  262. Tanaka M, Machida Y, Niu S, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004;10(2):148–54.

    Article  PubMed  CAS  Google Scholar 

  263. Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 2006;172(5):719–31.

    Article  PubMed  CAS  Google Scholar 

  264. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007;282(8):5641–52.

    Article  PubMed  CAS  Google Scholar 

  265. Berger Z, Ravikumar B, Menzies FM, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 2006;15(3):433–42.

    Article  PubMed  CAS  Google Scholar 

  266. Sarkar S, Floto RA, Berger Z, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005;170(7):1101–11.

    Article  PubMed  CAS  Google Scholar 

  267. Sarkar S, Rubinsztein DC. Inositol and IP3 levels regulate autophagy: Biology and therapeutic speculations. Autophagy 2006;2(2):132–4.

    PubMed  CAS  Google Scholar 

  268. Menzies FM, Ravikumar B, Rubinsztein DC. Protective roles for induction of autophagy in multiple proteinopathies. Autophagy 2006;2(3):224–5.

    PubMed  CAS  Google Scholar 

  269. Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004;36(6):585–95.

    Article  PubMed  CAS  Google Scholar 

  270. Sarkar S, Krishna G, Imarisio S, Saiki S, O'Kane CJ, Rubinsztein DC. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet 2008;17(2):170–8.

    Article  PubMed  CAS  Google Scholar 

  271. Zhang L, Yu J, Pan H, et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 2007;104(48):19023–8.

    Article  PubMed  CAS  Google Scholar 

  272. Williams A, Sarkar S, Cuddon P, et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol 2008;4(5):295–305.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Alabama, Birmingham, AL 35294, USA

    Qiuli Liang & Jianhua Zhang

Authors
  1. Qiuli Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianhua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianhua Zhang .

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Liang, Q., Zhang, J. (2009). Apoptosis in Neurodegenerative Diseases. In: Dong, Z., Yin, XM. (eds) Essentials of Apoptosis. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-381-7_21

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation