NeuroMolecular Medicine

, Volume 4, Issue 1–2, pp 21–35 | Cite as

Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases

  • Makoto Hashimoto
  • Edward Rockenstein
  • Leslie Crews
  • Eliezer Masliah
Article

Abstract

Abnormal interactions and misfolding of synaptic proteins in the nervous system are being extensively explored as important pathogenic events resulting in neurodegeneration in various neurological disorders. These include Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). In AD, misfolded amyloid β peptide 1–42 (Aβ), a proteolytic product of amyloid precursor protein metabolism, accumulates in the neuronal endoplasmic reticulum and extracellularly as plaques. In contrast, in PD and DLB cases there is abnormal accumulation of α-synuclein in neuronal cell bodies, axons, and synapses. Furthermore, in DLB, Aβ 1–42 may promote α-synuclein accumulation and neurodegeneration. The central event leading to synaptic and neuronal loss in these diseases is not completely clear yet; however, recent advances in the field suggest that nerve damage might result from the conversion of nontoxic monomers to toxic oligomers and protofibrils. The mechanisms by which misfolded Aβ peptide and α-synuclein might lead to synapse loss are currently under investigation. Several lines of evidence support the possibility that Aβ peptide and α-synuclein might interact to cause mitochondrial and plasma membrane damage upon translocation of protofibrils to the membranes. Accumulation of Aβ and α-synuclein oligomers in the mitochondrial membrane might result in the release of cytochrome C with the subsequent activation of the apoptosis cascade. Conversely, the oxidative stress and mitochondrial dysfunction associated with AD and PD may also lead to increased membrane permeability and cytochrome C release, which promotes Aβ and α-synuclein oligomerization and neurodegeneration. Together, these studies suggest that the translocation of misfolded proteins to the mitochondrial membrane might play an important role in either triggering or perpetuating neurodegeneration. The insights obtained from the characterization of this process may be applied to the role of mitochondrial dysfunction in other neurodegenerative disorders, including AD. New evidence may also provide a rationale for the mitochondrial membrane as a target for therapy in a variety of neurodegenerative diseases.

Index Entries

Alzheimer’s disease dementia with Lewy bodies α-synuclein synapse damage mitochondrial dysfunction protein misfolding aggregation oligomers plasma membrane 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alves Da Costa C., Ancolio K., and Checler F. (2000) Wild-type but not Parkinson’s disease-related ala-53→Thr mutant alpha synuclein protects neuronal cells from apoptotic stimuli. J. Biol. Chem. 275, 24065–24069.CrossRefGoogle Scholar
  2. Askanas V., McFerrin J., Baque S., et al. (1996) Transfer of β-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultures of normal human muscle. Proc. Natl. Acad. Sci. USA 93, 1314–1319.PubMedCrossRefGoogle Scholar
  3. Avila J., Lim, F., Moreno F. et al. (2002) Tau function and dysfunction in neurons: its role in neuro-degenerative disorders. Mol. Neurobiol. 25, 213–231.PubMedCrossRefGoogle Scholar
  4. Betarbet R., Sherer T. B., MacKenzie G., et al. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301–1306.PubMedCrossRefGoogle Scholar
  5. Bonifati V., Rizzu P., van Baren M. J., et al. (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259.PubMedCrossRefGoogle Scholar
  6. Busciglio J., Pelsman A., Wong C., et al. (2002) Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down’s syndrome. Neuron 33, 677–688.PubMedCrossRefGoogle Scholar
  7. Bush A. I. (2002) Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol. Aging 23, 1031–1038.PubMedCrossRefGoogle Scholar
  8. Chan S. L., Furukawa K., and Mattson M. P. (2002) Presenilins and APP in neuritic and synaptic plasticity: implications for the pathogenesis of Alzheimer’s disease. Neuromol. Med. 2, 167–196.CrossRefGoogle Scholar
  9. Chartier-Harlin M.-C., Crawford F., Houlden H., et al. (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846.PubMedCrossRefGoogle Scholar
  10. Conway K., Harper J., and Lansbury P. (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4, 1318–1320.PubMedCrossRefGoogle Scholar
  11. Conway K. A., Lee S. J., Rochet J. C., et al. (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc. Natl. Acad. Sci. USA 97, 571–576.PubMedCrossRefGoogle Scholar
  12. Cummings C. J. and Zoghbi H. Y. (2000) Trinucleotide repeats: mechanisms and pathophysiology. Annu. Rev. Genomics Hum. Genet. 1, 281–328.PubMedCrossRefGoogle Scholar
  13. Dauer W., Kholodilov N., Vila M., et al. (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc. Natl. Acad. Sci. USA 99, 14524–14529.PubMedCrossRefGoogle Scholar
  14. Duff K., Eckman C., Zehr C., et al. (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.PubMedCrossRefGoogle Scholar
  15. Feany M. and Bender W. (2000) A Drosophila model of Parkinson’s disease. Nature 404, 394–398.PubMedCrossRefGoogle Scholar
  16. Ferrigno P. and Silver P. (2000) Polyglutamine expansions: proteolysis, chaperones, and the dangers of promiscuity. Neuron 26, 9–12.PubMedCrossRefGoogle Scholar
  17. Fujiwara H., Hasegawa M., Dohmae N., et al. (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164.PubMedCrossRefGoogle Scholar
  18. Gearing M., Mirra S., Hedreen J., et al. (1995) Neuropathology confirmation of the clinical diagnosis of Alzheimer’s disease: CERAD. Part X. Neurology 45, 461–466.PubMedGoogle Scholar
  19. Giasson B. I., Duda J. E., Murray I. V., et al. (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290, 985–989.PubMedCrossRefGoogle Scholar
  20. Goate A., Chartier-Harlin M.-C., Mullan M., et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704.PubMedCrossRefGoogle Scholar
  21. Good P. F., Werner P., Hsu A., Olanow C. W., and Perl D. P. (1996) Evidence of neuronal oxidative damage in Alzheimer’s disease. Am. J. Pathol. 149, 21–28.PubMedGoogle Scholar
  22. Gosavi N., Lee H. J., Lee J. S., Patel S., and Lee S. J. (2002) Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J. Biol. Chem. 277, 48984–48992.PubMedCrossRefGoogle Scholar
  23. Haas C., Hung A. Y., Citron M., Teplow D. B., and Selkoe D. J. (1995) beta-Amyloid, protein processing and Alzheimer’s disease. Arzneimittelforschung 45, 398–402.PubMedGoogle Scholar
  24. Hashimoto M., and Masliah E. (1999) Alpha-synuclein in Lewy body disease and Alzheimer’s disease. Brain Pathol. 9, 707–720.PubMedCrossRefGoogle Scholar
  25. Hashimoto M., Takeda A., Hsu L. J., Takenouchi T., and Masliah E. (1999a) Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease. J. Biol. Chem. 274, 28849–28852.PubMedCrossRefGoogle Scholar
  26. Hashimoto M., Hsu L., Xia Y., et al. (1999b) Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro. Neuroreport 10, 717–721.PubMedCrossRefGoogle Scholar
  27. Hashimoto M., Hernandez-Ruiz S., Hsu L., et al. (1998) Human recombinant NACP/a-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease. Brain Res 799, 301–306PubMedCrossRefGoogle Scholar
  28. Hensley K., Carney J. M., Mattson M. P., et al. (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Natl. Acad. Sci. USA 91, 3270–3274.PubMedCrossRefGoogle Scholar
  29. Hod Y., Pentyala S. N., Whyard T. C., and El-Maghrabi M. R. (1999) Identification and characterization of a novel protein that regulates RNA-protein interaction. J. Cell Biochem. 72, 435–444.PubMedCrossRefGoogle Scholar
  30. Hsu L. J., Sagara Y., Arroyo A., et al. (2000) α-Synuclein promotes mitochondrial deficiencies and oxidative stress. Am. J. Pathol. 157, 401–410.PubMedGoogle Scholar
  31. Imai Y., Soda M., Inoue H., et al. (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902.PubMedCrossRefGoogle Scholar
  32. Irizarry M., Growdon W., Gomez-Isla T., et al. (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57, 334–337.PubMedGoogle Scholar
  33. Iwai A. (2000) Properties of NACP/alpha-synuclein and its role in Alzheimer’s disease. Biochim. Biophys. Acta 1502, 95–109.PubMedGoogle Scholar
  34. Iwai A., Masliah E., Yoshimoto M., et al. (1994) The precursor protein of non-Ab component of Alzheimer’s disease amyloid (NACP) is a presynaptic protein of the central nervous system. Neuron 14, 467–475.CrossRefGoogle Scholar
  35. Jakes R., Spillantini M., and Goedert M. (1994) Identification of two distinct synucleins from human brain. FEBS Lett. 345, 27–32.PubMedCrossRefGoogle Scholar
  36. Jenner P. (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov. Disord. 13, 24–34.PubMedGoogle Scholar
  37. Jia T., Liu Y. E., Liu J., and Shi Y. E. (1999) Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res. 59, 742–747.PubMedGoogle Scholar
  38. Jo E., McLaurin J., Yip C., St. George-Hyslop P., and Graser P. (2000) Alpha-synuclein membrane iteractions and lipid specificity. J. Biol. Chem. 275, 34328–34334.PubMedCrossRefGoogle Scholar
  39. Keller J. N., Kindy M. S., Holtsberg F. W., et al. (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J. Neurosci. 18, 687–697PubMedGoogle Scholar
  40. Keller J. N., Pang Z., Geddes J. W., et al. (1997) Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid beta-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J. Neurochem. Google Scholar
  41. Kirschenbaum F., Hsu S. C., Cordell B., and McCarthy J. V. (2001) Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276, 30701–30707.PubMedCrossRefGoogle Scholar
  42. Kish S. J., Bergeron C., Rajput A., et al. (1992) Brain cytochrome oxidase in Alzheimer’s disease. J. Neurochem. 59,, 776–779.PubMedCrossRefGoogle Scholar
  43. Kitada T., Asakawa S., Hattori N., et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608.PubMedCrossRefGoogle Scholar
  44. Klein R. L., King M. A., Hamby M. E., and Meyer E. M. (2002) Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther. 13, 605–612.PubMedCrossRefGoogle Scholar
  45. Koo E., Lansbury P. J., and Kelly J. (1999) Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc. Natl. Acad. Sci. USA 96, 9989–9990.PubMedCrossRefGoogle Scholar
  46. Kruger R., Kuhn W., Muller T., et al. (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat. Genet. 18, 106–108.PubMedCrossRefGoogle Scholar
  47. Langston J. W., Langston E. B., and Irwin I. (1984a) MPTP-induced parkinsonism in human and nonhuman primates—clinical and experimental aspects. Acta. Neurol. Scand. Suppl. 100, 49–54.PubMedGoogle Scholar
  48. Langston J. W., Forno L. S., Rebert C. S., and Irwin I. (1984b) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res. 292, 390–394.PubMedCrossRefGoogle Scholar
  49. Lansbury P. T. J. (1999) Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. Proc. Natl. Acad. Sci. USA 96, 3342–3344.PubMedCrossRefGoogle Scholar
  50. Lee H. J., Shin S. Y., Choi C., Lee Y. H., and Lee S. J. (2002) Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J. Biol. Chem. 277, 5411–5417.PubMedCrossRefGoogle Scholar
  51. Leroy E., Boyer R., Auburger G., et al. (1998) The ubiquitin pathway in Parkinsons’s disease. Nature 395, 451–452.PubMedCrossRefGoogle Scholar
  52. Liu Y., Fallon L., Lashuel H. A., Liu Z., and Lansbury P. T. J. (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111, 209–218.PubMedCrossRefGoogle Scholar
  53. Manning-Bog A. B., McCormack A. L., Purisai M. G., Bolin L. M., and Di Monte D. A. (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J. Neurosci. 23, 3095–3099.PubMedGoogle Scholar
  54. Masliah E. (2001) Recent advances in the understanding of the role of synaptic proteins in Alzheimer’s disease and other neurodegenerative disorders. IJ. Alz. Dis. 3, 1–9.Google Scholar
  55. Masliah E. (2000) The role of synaptic proteins in Alzheimer’s disease. Ann. NY Acad. Sci. 924, 68–75.PubMedCrossRefGoogle Scholar
  56. Masliah E., Rockenstein E., Veinbergs I., et al. (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 287, 1265–1269.PubMedCrossRefGoogle Scholar
  57. Masliah E., Iwai A., Mallory M., Ueda K., Saitoh T (1996) Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease. Am. J. Pathol. 148, 201–210.PubMedGoogle Scholar
  58. Masliah E., Rockenstein E., Veinbergs I., et al. (2001) β amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s and Parkinson’s disease. Proc. Natl. Acad. Sci. USA 98, 12245–12250.PubMedCrossRefGoogle Scholar
  59. Mitsumoto A., Nakagawa Y., Takeuchi A., et al. (2001) Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat. Free Radic. Res. 35, 301–310.PubMedCrossRefGoogle Scholar
  60. Mizuno Y., Ikebe S., Hattori N., et al. (1995) Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim. Biophys. Acta. 1271, 265–274.PubMedGoogle Scholar
  61. Muchowski P. J. (2002) Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron 35, 9–12.PubMedCrossRefGoogle Scholar
  62. Nagakubo D., Taira T., Kitaura H., et al. (1997) DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem. Biophys. Res. Commun. 231, 509–513.PubMedCrossRefGoogle Scholar
  63. Nakajo S., Tsukada K., Omata K., Nakamura Y., and Nakaya K. (1993) A new brain-specific 14-kDa protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosphorylation. Eur. J. Biochem. 217, 1057–1063.PubMedCrossRefGoogle Scholar
  64. Narayanan V. and Scarlata S. (2001) Membrane binding and self-association of alpha-synucleins. Biochemistry 40, 9927–9934.PubMedCrossRefGoogle Scholar
  65. Negro A., Brunati A. M., Donella-Deana A., Massimino M. L., and Pinna L. A. (2002) Multiple phosphorylation of alpha-synuclein by protein tyrosine kinase Syk prevents eosin-induced aggregation. FASEB J. 16, 210–212.PubMedGoogle Scholar
  66. Orth M. and Schapira A. H. (2001) Mitochondria and degenerative disorders. Am. J. Med. Genet. 106, 27–36.PubMedCrossRefGoogle Scholar
  67. Osterova-Golts N., Petrucelli L., Hardy J., et al. (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048–6054.Google Scholar
  68. Ostrerova N., Petrucelli L., Farrer M., et al. (1999) alpha-synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci. 19, 5782–5791.PubMedGoogle Scholar
  69. Paik S. R., Shin H. J., Lee J. H., Chang C. S., and Kim J. (1999) Copper(II)-induced self-oligomerization of alpha-synuclein. Biochem. J. 340, 821–828.PubMedCrossRefGoogle Scholar
  70. Parker W. D. J., Filley C. M., and Parks J. K. (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 40, 1302–1303.PubMedGoogle Scholar
  71. Perrin R., Woods W., Clayton D., and George J. (2000) Interaction of human alpha-synuclein and Parkinson’s disease variants with phospholipids: structural analysis using site-directed mutagenesis. J. Biol. Chem. 275, 34393–34398.PubMedCrossRefGoogle Scholar
  72. Petrucelli L., O’Farrell C., Lockhart P. J., et al. (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36, 1007–1019.PubMedCrossRefGoogle Scholar
  73. Pfanner N. and Meijer M (1997) The Tom and Tim machine. Curr. Biol. 7, 100–103.CrossRefGoogle Scholar
  74. Polymeropoulos M., Lavedan C., Leroy E., et al. (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047.PubMedCrossRefGoogle Scholar
  75. Ramassamy C., Averill D., Beffert U., et al. (1999) Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer’s disease is related to the apolipoprotein E genotype. Free Radic. Biol. Med. 27, 544–553.PubMedCrossRefGoogle Scholar
  76. Rochet J., Conway K., and Lansbury P. J. (2000) Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse α-synuclein. Biochemistry 39, 10619–10626.PubMedCrossRefGoogle Scholar
  77. Rockenstein E., Mallory M., Hashimoto M., et al. (2002) Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J. Neurosci. Res. 68, 568–578.PubMedCrossRefGoogle Scholar
  78. Schapira A. H., Gu M., Taanman J. W., et al. (1998) Mitochondria in the etiology and pathogenesis of Parkinson’s disease. Ann. Neurol. 44, S89–98.PubMedGoogle Scholar
  79. Selkoe D. J., Yamazaki T., Citron M., et al. (1996) The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann. NY Acad. Sci. 777, 57–64.PubMedCrossRefGoogle Scholar
  80. Serpell L., Berriman J., Jakes R., Goedert M., and Crowther R. (2000) Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformation. Proc. Natl. Acad. Sci. USA 97, 4897–4902.PubMedCrossRefGoogle Scholar
  81. Sherer T. B., Kim J. H., Betarbet R., and Greenamyre J. T. (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp. Neurol. 179, 9–16.PubMedCrossRefGoogle Scholar
  82. Shigenaga M., Hagen T., and Ames B. (1994) Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA 91, 10771–10778.PubMedCrossRefGoogle Scholar
  83. Shimura H., Hattori N., Kubo S.-I., et al. (2000) Familialr Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302–305.PubMedCrossRefGoogle Scholar
  84. Smith M. A., Perry G., Richey P. L., et al. (1996) Oxidative damage in Alzheimer’s. Nature 382, 120–121.PubMedCrossRefGoogle Scholar
  85. Song D., Shults C., Sisk A., Rockenstein E., and Masliah E. (2003) Enhanced Sustantia Nigra Pathology in human α-synuclein Transgenic Mice after treatment with MPTP. Exp. Neurol., in press.Google Scholar
  86. Souza J., Giasson B., Chen Q., Lee V.-Y., and Ischiropoulos H. (2000) Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. J. Biol. Chem. 275, 18344–18349.PubMedCrossRefGoogle Scholar
  87. Spillantini M., Schmidt M., Lee V.-Y., et al. (1997) α-Synuclein in Lewy bodies. Nature 388, 839–840.PubMedCrossRefGoogle Scholar
  88. Surguchov A., Surgucheva I., Solessio E., and Baehr W. (1999) Synoretin—A new protein belonging to the synuclein family. Mol. Cell Neurosci. 13, 95–103.PubMedCrossRefGoogle Scholar
  89. Swerdlow R. H., Parks J. K., Cassarino D. S., et al. (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49, 918–925.PubMedGoogle Scholar
  90. Takeda A., Mallory M., Sundsmo M., et al. (1998a) Abnormal accumulation of NACP / α-synuclein in neurodegenerative disorders. Am. J. Pathol. 152, 367–372.PubMedGoogle Scholar
  91. Takeda A., Hashimoto M., Mallory M., et al. (1998b) Abnormal distribution of the non-Ab component of Alzheimer’s disease amyloid precursor/α-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. Lab. Invest. 78, 1169–1177.PubMedGoogle Scholar
  92. Tanaka Y., Engelender S., Igarashi S., et al. (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum. Mol. Genet. 10, 919–926.PubMedCrossRefGoogle Scholar
  93. Terry R., Hansen L., and Masliah E. (1994) Structural basis of the cognitive alterations in Alzheimer disease. In: Alzheimer Disease (Terry R., Katzman R., eds.), Raven Press, New York, pp. 179–196.Google Scholar
  94. Trojanowski J. and Lee V. (1998) Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for pathogenesis of Parkinson disease and Lewy body dementia. Arch. Neurol. 55, 151–152.PubMedCrossRefGoogle Scholar
  95. Trojanowski J., Goedert M., Iwatsubo T., and Lee V. (1998) Fatal attractions: abnormal protein aggregation and neuron death in Parkinson’s disease and lewy body dementia. Cell Death Differ. 5, 832–837.PubMedCrossRefGoogle Scholar
  96. Trojanowski J. Q. and Lee V. M. (2000) “Fatal attractions” of proteins. A comprehensive hypothetical mechanism underlying Alzheimer’s disease and other neurodegenerative disorders. Ann. N Y Acad. Sci. 924, 62–67.PubMedCrossRefGoogle Scholar
  97. Ueda K., Masliah E., Xia Y., et al. (1993) Novel amyloid component (NAC) differentiates Alzheimer’s disease from normal aging plaques. Soc. Neurosci. Abstr. 19, 1254.Google Scholar
  98. Volles M. J. and Lansbury P. T., Jr. (2002) Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41, 4595–4602.PubMedCrossRefGoogle Scholar
  99. Volles M. J., Lee S. J., Rochet J. C., et al. (2001) Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 40, 7812–7819.PubMedCrossRefGoogle Scholar
  100. Wagenfeld A., Gromoll J., and Cooper T. G. (1998) Molecular cloning and expression of rat contraception associated protein 1 (CAP1), a protein putatively involved in fertilization. Biochem. Biophys. Res. Commun. 251, 545–549.PubMedCrossRefGoogle Scholar
  101. Wakabayashi K., Hansen L., Vincent I., Mallory M., and Masliah E. (1997) Neurofibrillary tangles in the dentate granule cells in Alzheimer’s disease, Lewy body disease and progressive supranuclear palsy. Acta. Neuropathol. 93, 7–12.PubMedCrossRefGoogle Scholar
  102. Walsh D., Tseng B., Rydel R., Podlisny M., and Selkoe D. (2000) The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 39, 10831–10839.PubMedCrossRefGoogle Scholar
  103. Weinreb P., Zhen W., Poon A., Conway K., and Lansbury P. J. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35, 13709–13715.PubMedCrossRefGoogle Scholar
  104. Wood S. J., Wypych J., Steavenson S., et al. (1999) α-Synuclein fibrillogenesis is nucleation dependent. Implications for the pathogenesis of Parkinson’s disease. J. Biol. Chem. 274, 19509–19512.PubMedCrossRefGoogle Scholar
  105. Yamin G., Glaser C. B., Uversky V. N., and Fink A. L. (2003) Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. J. Biol. Chem. 278, 27630–27635. Epub 2003 May 16.PubMedCrossRefGoogle Scholar
  106. Yang F., Ueda K., Chen P., Ashe K. H., and Cole G. M. (2000) Plaque-associated alpha-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein. Brain Res. 853, 381–383.PubMedCrossRefGoogle Scholar
  107. Youdim M. B., Ben-Shachar D., Riederer P. (1994) The enigma of neuromelanin in Parkinson’s disease substantia nigra. J. Neural. Transm. Suppl. 43, 113–122.PubMedGoogle Scholar
  108. Younkin S. G. (1997) The AAP and PS1/2 mutations linked to early onset familial Alzheimer’s disease increase the extracellular concentration and A beta 1–42 (43). Rinsho. Shinkeigaku. 37, 1099.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Makoto Hashimoto
    • 1
  • Edward Rockenstein
    • 1
  • Leslie Crews
    • 1
  • Eliezer Masliah
    • 1
    • 2
  1. 1.Department of NeurosciencesUniversity of CaliforniaSan Diego, La Jolla
  2. 2.Department of PathologyUniversity of CaliforniaSan Diego, La Jolla

Personalised recommendations