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PMID: 19538146 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Biophysics of Parkinson's disease: structure and aggregation of alpha-synuclein.

Current protein & peptide science ·Vol. 10 ·No. 5 ·2009-10-00 ·Pages 483-99

Uversky VN, Eliezer D

Abstract

Parkinson's disease (PD) is a slowly progressive movement disorder that results from the loss of dopaminergic neurons in the substantia nigra, a small area of cells in the mid-brain. PD is a multifactorial disorder with unknown etiology, in which both genetic and environmental factors play important roles. Substantial evidence links alpha-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic PD. Rare familial cases of PD are associated with missense point mutations in alpha-synuclein, or with the hyper-expression of the wild type protein due to its gene duplication/triplication. Furthermore, alpha-synuclein was identified as the major component of amyloid fibrils found in Lewy body and Lewy neurites, the characteristic proteinaceous deposits that are the diagnostic hallmarks of PD. alpha-Synuclein is abundant in various regions of the brain and has two closely related homologs, beta-synuclein and gamma-synuclein. When isolated in solution, the protein is intrinsically disordered, but in the presence of lipid surfaces alpha-synuclein adopts a highly helical structure that is believed to mediate its normal function(s). A number of different conformational states of alpha-synuclein have been observed. Besides the membrane-bound form, other critical conformations include a partially-folded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. A number of intrinsic and extrinsic factors that either accelerate or inhibit the rate of alpha-synuclein aggregation and fibrillation in vitro are known. There is a strong correlation between the conformation of alpha-synuclein (induced by various factors) and its rate of fibrillation. The aggregation process appears to be branched, with one pathway leading to fibrils and another to oligomeric intermediates that may ultimately form amorphous deposits. The molecular basis of Parkinson's disease appears to be tightly coupled to the aggregation of alpha-synuclein and the factors that affect its conformation. This review focuses on the contributions of Prof. Anthony L. Fink to the field and presents some recent developments in this exciting area.

MeSH Terms
Animals Biophysics/methods Dementia/metabolism Humans Magnetic Resonance Spectroscopy Models, Biological Parkinson Disease/metabolism,pathology Protein Binding Protein Conformation Protein Folding alpha-Synuclein/chemistry,physiology
Chemicals
alpha-Synuclein
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Uversky Vladimir N
Institite for Intrinsically Disordered Protein Research, Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. vuversky@iupui.edu
Eliezer David
References (245)
245 references, click to expand
  1. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins.
    Biochemistry. 1998 Apr 7;37(14):4901-9 PMID: 9538008
  2. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.
    Science. 1997 Jun 27;276(5321):2045-7 PMID: 9197268
  3. Familial occurrence of amyotrophic lateral sclerosis, parkinsonism, and dementia.
    Ann Neurol. 1984 Dec;16(6):642-8 PMID: 6524873
  4. Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid.
    Biochemistry. 2000 Mar 14;39(10):2552-63 PMID: 10704204
  5. Trimethylamine-N-oxide-induced folding of alpha-synuclein.
    FEBS Lett. 2001 Nov 30;509(1):31-5 PMID: 11734201
  6. Changes in biomolecular conformation seen by small angle X-ray scattering.
    Chem Rev. 2001 Jun;101(6):1763-78 PMID: 11709998
  7. Description of Parkinson's disease as a clinical syndrome.
    Ann N Y Acad Sci. 2003 Jun;991:1-14 PMID: 12846969
  8. Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger.
    J Biol Chem. 1996 Mar 22;271(12):6839-44 PMID: 8636108
  9. Role of protein-water interactions and electrostatics in alpha-synuclein fibril formation.
    Biochemistry. 2004 Mar 23;43(11):3289-300 PMID: 15023080
  10. Oxidative alterations in Alzheimer's disease.
    Brain Pathol. 1999 Jan;9(1):133-46 PMID: 9989456
  11. Helix periodicity, topology, and dynamics of membrane-associated alpha-synuclein.
    Protein Sci. 2005 Apr;14(4):862-72 PMID: 15741347
  12. Clinical and pathological features in hydrocarbon-induced parkinsonism.
    Ann Neurol. 1996 Dec;40(6):922-5 PMID: 9007099
  13. Alpha-synuclein and Parkinson's disease.
    Cell Mol Life Sci. 2000 Dec;57(13-14):1894-908 PMID: 11215516
  14. Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles.
    J Am Chem Soc. 2008 Oct 1;130(39):12856-7 PMID: 18774805
  15. Hallervorden-Spatz syndrome and brain iron metabolism.
    Arch Neurol. 1991 Dec;48(12):1285-93 PMID: 1845035
  16. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration.
    Cell Tissue Res. 2004 Oct;318(1):225-41 PMID: 15258850
  17. The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins?
    Lancet Neurol. 2003 Sep;2(9):531-8 PMID: 12941575
  18. X-ray solution scattering studies of protein folding.
    Fold Des. 1996;1(5):R107-14 PMID: 9080178
  19. Inter-helix distances in lysophospholipid micelle-bound alpha-synuclein from pulsed ESR measurements.
    J Am Chem Soc. 2006 Aug 9;128(31):10004-5 PMID: 16881616
  20. The role of oxidative stress in Alzheimer disease.
    Arch Neurol. 1999 Dec;56(12):1449-52 PMID: 10593298
  21. Review: modulating factors in amyloid-beta fibril formation.
    J Struct Biol. 2000 Jun;130(2-3):259-70 PMID: 10940230
  22. Is the cause of Parkinson's disease environmental or hereditary? Evidence from twin studies.
    Adv Neurol. 2003;91:133-42 PMID: 12442672
  23. Solvent-induced collapse of alpha-synuclein and acid-denatured cytochrome c.
    Protein Sci. 2001 Nov;10(11):2195-9 PMID: 11604526
  24. Environmental factors and Parkinson's disease: a case-control study in China.
    Neurology. 1989 May;39(5):660-4 PMID: 2710356
  25. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
    J Neurosci. 2000 Jun 1;20(11):4050-8 PMID: 10818140
  26. Conformational behavior of human alpha-synuclein is modulated by familial Parkinson's disease point mutations A30P and A53T.
    Neurotoxicology. 2002 Oct;23(4-5):553-67 PMID: 12428728
  27. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome).
    J Neurol Sci. 1989 Dec;94(1-3):79-100 PMID: 2559165
  28. Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease.
    FASEB J. 2004 Jun;18(9):962-4 PMID: 15059976
  29. A broken alpha -helix in folded alpha -Synuclein.
    J Biol Chem. 2003 Apr 25;278(17):15313-8 PMID: 12586824
  30. Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers.
    FEBS Lett. 2003 May 8;542(1-3):147-52 PMID: 12729915
  31. GM1 specifically interacts with alpha-synuclein and inhibits fibrillation.
    Biochemistry. 2007 Feb 20;46(7):1868-77 PMID: 17253773
  32. Hallervorden-Spatz syndrome.
    Arch Neurol. 1974 Jan;30(1):70-83 PMID: 4808495
  33. Chain-like conformation of heat-denatured ribonuclease A and cytochrome c as evidenced by solution X-ray scattering.
    Fold Des. 1998;3(3):195-201 PMID: 9562549
  34. alpha-Synuclein locus triplication causes Parkinson's disease.
    Science. 2003 Oct 31;302(5646):841 PMID: 14593171
  35. Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology.
    Am J Pathol. 2000 Aug;157(2):361-8 PMID: 10934140
  36. Amyotrophic lateral sclerosis-Parkinsonism dementia complex of Guam: further genetic investigations.
    Am J Hum Genet. 1969 Mar;21(2):133-41 PMID: 5770171
  37. Expression of agrin in the developing and adult rat brain.
    Neuroscience. 1997 Jan;76(2):581-96 PMID: 9015340
  38. Amino acid determinants of alpha-synuclein aggregation: putting together pieces of the puzzle.
    FEBS Lett. 2002 Jul 3;522(1-3):9-13 PMID: 12095610
  39. Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest.
    Prostate. 2001 Dec 1;49(4):285-92 PMID: 11746275
  40. Guam: deadly disease dying out.
    Science. 1993 Jul 23;261(5120):424-6 PMID: 8332906
  41. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia.
    Brain. 1991 Aug;114 ( Pt 4):1953-75 PMID: 1832073
  42. Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein.
    J Biol Chem. 2003 Jul 25;278(30):27630-5 PMID: 12754258
  43. Quantification of alpha-synuclein binding to lipid vesicles using fluorescence correlation spectroscopy.
    Biophys J. 2006 Jun 15;90(12):4692-700 PMID: 16581836
  44. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains.
    J Neurochem. 1989 Feb;52(2):515-20 PMID: 2911028
  45. Familial Parkinson's disease. Alpha-synuclein and parkin.
    Adv Neurol. 2001;86:13-21 PMID: 11553970
  46. Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease.
    Neurotoxicology. 1999 Apr-Jun;20(2-3):239-47 PMID: 10385887
  47. NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease.
    Neurosci Lett. 1997 Dec 12;239(1):45-8 PMID: 9547168
  48. Occupational metal exposures and the risk of Parkinson's disease.
    Neuroepidemiology. 1999;18(6):303-8 PMID: 10545782
  49. The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation.
    J Biol Chem. 2003 Oct 10;278(41):40186-97 PMID: 12885775
  50. NMR mapping of copper binding sites in alpha-synuclein.
    Biochim Biophys Acta. 2006 Jan;1764(1):5-12 PMID: 16338184
  51. Zn(2+)-mediated structure formation and compaction of the "natively unfolded" human prothymosin alpha.
    Biochem Biophys Res Commun. 2000 Jan 19;267(2):663-8 PMID: 10631119
  52. Markers of protein oxidation by hydroxyl radical and reactive nitrogen species in tissues of aging rats.
    Am J Physiol. 1998 Feb;274(2):R453-61 PMID: 9486304
  53. Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies.
    J Biol Chem. 2000 Jun 16;275(24):18344-9 PMID: 10747881
  54. The E46K mutation in alpha-synuclein increases amyloid fibril formation.
    J Biol Chem. 2005 Mar 4;280(9):7800-7 PMID: 15632170
  55. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein.
    J Biol Chem. 2002 Jan 18;277(3):1641-4 PMID: 11707429
  56. Interaction of human alpha-Synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis.
    J Biol Chem. 2000 Nov 3;275(44):34393-8 PMID: 10952980
  57. Parkinson's disease mortality and the industrial use of heavy metals in Michigan.
    Mov Disord. 1993;8(1):87-92 PMID: 8419812
  58. Genetics of Parkinson disease: paradigm shifts and future prospects.
    Nat Rev Genet. 2006 Apr;7(4):306-18 PMID: 16543934
  59. Residual structure and dynamics in Parkinson's disease-associated mutants of alpha-synuclein.
    J Biol Chem. 2001 Dec 7;276(49):45996-6003 PMID: 11590151
  60. Dementia-Parkinsonism syndrome with numerous Lewy bodies and senile plaques in cerebral cortex.
    Arch Psychiatr Nervenkr (1970). 1979 Apr 12;226(4):241-50 PMID: 222231
  61. Effects of nitration on the structure and aggregation of alpha-synuclein.
    Brain Res Mol Brain Res. 2005 Mar 24;134(1):84-102 PMID: 15790533
  62. Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin.
    Anticancer Res. 2000 Sep-Oct;20(5A):2861-5 PMID: 11062694
  63. Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease.
    Neuropharmacology. 2003 Jul;45(1):14-44 PMID: 12814657
  64. Lipid binding inhibits alpha-synuclein fibril formation.
    J Biol Chem. 2003 May 9;278(19):16873-7 PMID: 12621030
  65. Accelerated alpha-synuclein fibrillation in crowded milieu.
    FEBS Lett. 2002 Mar 27;515(1-3):99-103 PMID: 11943202
  66. Intrinsically unstructured proteins and their functions.
    Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208 PMID: 15738986
  67. Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation.
    J Biol Chem. 1998 Oct 9;273(41):26292-4 PMID: 9756856
  68. Multiple-system atrophy: a new alpha-synuclein disease?
    Lancet. 1998 Aug 15;352(9127):547-8 PMID: 9716068
  69. Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis.
    J Neurochem. 1991 Feb;56(2):446-51 PMID: 1988548
  70. Dementia with Lewy bodies.
    Lancet Neurol. 2004 Jan;3(1):19-28 PMID: 14693108
  71. Stabilization of partially folded conformation during alpha-synuclein oligomerization in both purified and cytosolic preparations.
    J Biol Chem. 2001 Nov 23;276(47):43495-8 PMID: 11590163
  72. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
    Nat Genet. 1998 Feb;18(2):106-8 PMID: 9462735
  73. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure.
    J Immunol. 1998 Sep 1;161(5):2524-32 PMID: 9725252
  74. Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies.
    Acta Neuropathol. 2000 Nov;100(5):568-74 PMID: 11045680
  75. The etiopathogenesis of Parkinson disease and suggestions for future research. Part I.
    J Neuropathol Exp Neurol. 2007 Apr;66(4):251-7 PMID: 17413315
  76. Cellular pathology in multiple system atrophy.
    Neuropathology. 2006 Aug;26(4):338-45 PMID: 16961071
  77. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13.
    Nat Genet. 1996 Dec;14(4):479-81 PMID: 8944032
  78. The hydroxyl radical in lens nuclear cataractogenesis.
    J Biol Chem. 1998 Oct 30;273(44):28603-9 PMID: 9786852
  79. Structure and dynamics of micelle-bound human alpha-synuclein.
    J Biol Chem. 2005 Mar 11;280(10):9595-603 PMID: 15615727
  80. The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states.
    Biochemistry. 2007 Jun 19;46(24):7107-18 PMID: 17530780
  81. Electron microscopic study of the developing neuroblast of the dorsal root ganglion of the rabbit embryo.
    J Comp Neurol. 1965 Jun;124(3):267-317 PMID: 5325036
  82. Protective effects of flavonoids in the roots of Scutellaria baicalensis Georgi against hydrogen peroxide-induced oxidative stress in HS-SY5Y cells.
    Pharmacol Res. 2001 Feb;43(2):173-8 PMID: 11243719
  83. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73 PMID: 9600990
  84. Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia.
    Cell Death Differ. 1998 Oct;5(10):832-7 PMID: 10203692
  85. Amyloid ion channels: a porous argument or a thin excuse?
    J Gen Physiol. 2006 Dec;128(6):631-3 PMID: 17130516
  86. Aluminum-containing antacids as a cause of idiopathic Parkinson's disease.
    Med Hypotheses. 1999 Jul;53(1):22-3 PMID: 10499820
  87. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity.
    Am J Epidemiol. 2003 Jun 1;157(11):1015-22 PMID: 12777365
  88. Estimation of macromolecule concentrations and excluded volume effects for the cytoplasm of Escherichia coli.
    J Mol Biol. 1991 Dec 5;222(3):599-620 PMID: 1748995
  89. The effect of macromolecular crowding on protein aggregation and amyloid fibril formation.
    J Mol Recognit. 2004 Sep-Oct;17(5):456-64 PMID: 15362105
  90. Distribution and substrate properties of agrin, a heparan sulfate proteoglycan of developing axonal pathways.
    J Comp Neurol. 1997 Jun 23;383(1):1-17 PMID: 9184982
  91. Alpha-synuclein in Lewy bodies.
    Nature. 1997 Aug 28;388(6645):839-40 PMID: 9278044
  92. Oxidative stress in Huntington's disease.
    Brain Pathol. 1999 Jan;9(1):147-63 PMID: 9989457
  93. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy.
    Neurosci Lett. 1998 Jun 19;249(2-3):180-2 PMID: 9682846
  94. Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies.
    J Neuropathol Exp Neurol. 2006 Mar;65(3):278-88 PMID: 16651889
  95. Rifampicin prevents the aggregation and neurotoxicity of amyloid beta protein in vitro.
    Biochem Biophys Res Commun. 1994 Oct 14;204(1):76-83 PMID: 7945395
  96. Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro.
    J Biol Chem. 1999 Mar 19;274(12):7619-22 PMID: 10075647
  97. [Environmental factors in the etiology of Parkinson's disease].
    Can J Neurol Sci. 1990 Aug;17(3):286-91 PMID: 2207882
  98. Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication.
    Brain. 2004 Apr;127(Pt 4):768-72 PMID: 14736756
  99. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.
    Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10540-3 PMID: 1683703
  100. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system.
    Neuron. 1995 Feb;14(2):467-75 PMID: 7857654
  101. DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation.
    PLoS Biol. 2004 Nov;2(11):e362 PMID: 15502874
  102. Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation.
    Glycobiology. 2005 Dec;15(12):1320-31 PMID: 16037493
  103. What does it mean to be natively unfolded?
    Eur J Biochem. 2002 Jan;269(1):2-12 PMID: 11784292
  104. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications.
    Ann Neurol. 2004 Feb;55(2):174-9 PMID: 14755720
  105. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree--a new disease?
    Clin Neuropathol. 1984 Sep-Oct;3(5):185-92 PMID: 6094067
  106. Alpha-synuclein and neurodegenerative diseases.
    Nat Rev Neurosci. 2001 Jul;2(7):492-501 PMID: 11433374
  107. beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor.
    Neuron. 2001 Oct 25;32(2):213-23 PMID: 11683992
  108. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders.
    Science. 2000 Feb 18;287(5456):1265-9 PMID: 10678833
  109. Interface between tauopathies and synucleinopathies: a tale of two proteins.
    Ann Neurol. 2006 Mar;59(3):449-58 PMID: 16489609
  110. Climbing the scaffolds of Parkinson's disease pathogenesis.
    Neuron. 2007 Feb 15;53(4):469-70 PMID: 17296545
  111. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders.
    Annu Rev Neurosci. 2003;26:267-98 PMID: 12704221
  112. Environmental factors in Parkinson's disease.
    Neurotoxicology. 2002 Oct;23(4-5):487-502 PMID: 12428721
  113. A population-based investigation of Parkinson's disease with and without dementia. Relationship to age and gender.
    Arch Neurol. 1992 May;49(5):492-7 PMID: 1580811
  114. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein.
    Ann Neurol. 1998 Sep;44(3):415-22 PMID: 9749615
  115. Molecular crowding accelerates fibrillization of alpha-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease?
    Biochemistry. 2002 Mar 26;41(12):3855-60 PMID: 11900526
  116. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death.
    Nature. 2004 Oct 14;431(7010):805-10 PMID: 15483602
  117. Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders.
    Am J Pathol. 1998 Feb;152(2):367-72 PMID: 9466562
  118. Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein.
    FEBS Lett. 2004 Oct 22;576(3):363-8 PMID: 15498564
  119. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure.
    J Biol Chem. 2001 Nov 23;276(47):44284-96 PMID: 11553618
  120. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.
    Science. 2000 Nov 3;290(5493):985-9 PMID: 11062131
  121. Review: amyloidogenesis-unquestioned answers and unanswered questions.
    J Struct Biol. 2000 Jun;130(2-3):99-108 PMID: 10940218
  122. Polycation-induced oligomerization and accelerated fibrillation of human alpha-synuclein in vitro.
    Protein Sci. 2003 Apr;12(4):702-7 PMID: 12649428
  123. Neuropathology of Parkinson's disease.
    J Neuropathol Exp Neurol. 1996 Mar;55(3):259-72 PMID: 8786384
  124. Implications of macromolecular crowding for protein assembly.
    Curr Opin Struct Biol. 2000 Feb;10(1):34-9 PMID: 10679465
  125. Occurrence of human alpha-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer's disease.
    J Neurol Sci. 2000 Mar 15;174(2):81-4 PMID: 10727692
  126. Agrin is a heparan sulfate proteoglycan.
    J Biol Chem. 1995 Feb 17;270(7):3392-9 PMID: 7852425
  127. Guiding protein aggregation with macromolecular crowding.
    Biochemistry. 2008 Aug 26;47(34):8993-9006 PMID: 18665616
  128. Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion.
    J Neuropathol Exp Neurol. 1961 Apr;20:237-44 PMID: 13730588
  129. Synucleinopathies: clinical and pathological implications.
    Arch Neurol. 2001 Feb;58(2):186-90 PMID: 11176955
  130. Anion-induced folding of Staphylococcal nuclease: characterization of multiple equilibrium partially folded intermediates.
    J Mol Biol. 1998 May 15;278(4):879-94 PMID: 9614949
  131. Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):13990-5 PMID: 12374847
  132. Acanthocytosis, retinitis pigmentosa, pallidal degeneration. Report of two cases without serum lipid abnormalities.
    J Neurol Sci. 1996 Sep 1;140(1-2):129-31 PMID: 8866438
  133. Soluble amyloid oligomers increase bilayer conductance by altering dielectric structure.
    J Gen Physiol. 2006 Dec;128(6):637-47 PMID: 17101816
  134. Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure.
    J Neurol. 1999 Mar;246(3):198-206 PMID: 10323318
  135. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.
    Ann Neurol. 2004 Feb;55(2):164-73 PMID: 14755719
  136. Evidence for a partially folded intermediate in alpha-synuclein fibril formation.
    J Biol Chem. 2001 Apr 6;276(14):10737-44 PMID: 11152691
  137. Advanced oxidation protein products: oxidative stress markers and mediators of inflammation in uremia.
    Adv Nephrol Necker Hosp. 1998;28:321-41 PMID: 9889997
  138. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies.
    Am J Pathol. 2000 Nov;157(5):1439-45 PMID: 11073803
  139. Nuclear localization of alpha-synuclein and its interaction with histones.
    Biochemistry. 2003 Jul 22;42(28):8465-71 PMID: 12859192
  140. The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.
    Ann N Y Acad Sci. 2000;920:16-27 PMID: 11193145
  141. Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat.
    Neurobiol Dis. 2002 Jul;10(2):119-27 PMID: 12127150
  142. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism.
    Neurology. 1985 Feb;35(2):227-34 PMID: 3969211
  143. Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies.
    Behav Brain Res. 2000 Aug;113(1-2):117-20 PMID: 10942038
  144. Alpha-synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation.
    Brain Res. 2001 Jan 12;888(2):287-296 PMID: 11150486
  145. The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils.
    J Biol Chem. 2004 Jun 25;279(26):26846-57 PMID: 15096521
  146. Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin.
    Science. 1987 Jul 31;237(4814):517-22 PMID: 3603037
  147. Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany.
    Neurology. 1996 May;46(5):1275-84 PMID: 8628466
  148. Role of individual methionines in the fibrillation of methionine-oxidized alpha-synuclein.
    Biochemistry. 2004 Apr 20;43(15):4621-33 PMID: 15078109
  149. Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies.
    Philos Trans R Soc Lond B Biol Sci. 1999 Jun 29;354(1386):1101-18 PMID: 10434313
  150. Methionine oxidation inhibits fibrillation of human alpha-synuclein in vitro.
    FEBS Lett. 2002 Apr 24;517(1-3):239-44 PMID: 12062445
  151. Concerted action of metals and macromolecular crowding on the fibrillation of alpha-synuclein.
    Protein Pept Lett. 2008;15(10):1079-85 PMID: 19075819
  152. Familial aggregation of amyotrophic lateral sclerosis, dementia, and Parkinson's disease: evidence of shared genetic susceptibility.
    Neurology. 1994 Oct;44(10):1872-7 PMID: 7936240
  153. Synergistic effects of pesticides and metals on the fibrillation of alpha-synuclein: implications for Parkinson's disease.
    Neurotoxicology. 2002 Oct;23(4-5):527-36 PMID: 12428725
  154. Protein-protein interactions of alpha-synuclein in brain homogenates and transfected cells.
    Brain Res Mol Brain Res. 2001 Nov 1;95(1-2):138-45 PMID: 11687285
  155. Widespread occurrence of alpha-synuclein/NACP-immunoreactive neuronal inclusions in juvenile and adult-onset Hallervorden-Spatz disease with Lewy bodies.
    Neuropathol Appl Neurobiol. 1999 Oct;25(5):363-8 PMID: 10564525
  156. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct.
    Science. 2001 Nov 9;294(5545):1346-9 PMID: 11701929
  157. Role of oxygen free radicals in carcinogenesis and brain ischemia.
    FASEB J. 1990 Jun;4(9):2587-97 PMID: 2189775
  158. Molten globule of cytochrome c studied by small angle X-ray scattering.
    J Mol Biol. 1993 Feb 5;229(3):591-6 PMID: 8381874
  159. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation.
    J Biol Chem. 1999 Apr 2;274(14):9843-6 PMID: 10092675
  160. Occurrence of alpha-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex.
    Acta Neuropathol. 2004 Jun;107(6):497-503 PMID: 15024581
  161. Neurofibrillary tangles and senile plaques in brain of elderly leprosy patients.
    Lancet. 1992 Oct 17;340(8825):978 PMID: 1357384
  162. The synucleins.
    Genome Biol. 2002;3(1):REVIEWS3002 PMID: 11806835
  163. Lewy bodies in cerebral cortex, report of three cases.
    Acta Neuropathol. 1978 May 24;42(2):127-34 PMID: 654884
  164. Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins.
    J Biol Chem. 2002 Apr 5;277(14):11970-8 PMID: 11812782
  165. Age-related oxidation reaction in proteins.
    Toxicol Ind Health. 1993 Jan-Apr;9(1-2):187-96 PMID: 8093419
  166. Conformational properties of alpha-synuclein in its free and lipid-associated states.
    J Mol Biol. 2001 Apr 6;307(4):1061-73 PMID: 11286556
  167. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
    Neurology. 2005 Dec 27;65(12):1863-72 PMID: 16237129
  168. Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson's disease.
    FEBS Lett. 1998 Nov 27;440(1-2):67-70 PMID: 9862427
  169. Protein globularization during folding. A study by synchrotron small-angle X-ray scattering.
    J Mol Biol. 1996 Oct 4;262(4):559-74 PMID: 8893863
  170. Parkinsonism from methanol poisoning: benefit from treatment with anti-Parkinson drugs.
    Mov Disord. 1999 May;14(3):520-2 PMID: 10348484
  171. 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 U S A. 2000 Jan 18;97(2):571-6 PMID: 10639120
  172. Structural characterization of the molten globule of alpha-lactalbumin by solution X-ray scattering.
    Protein Sci. 1997 Feb;6(2):422-30 PMID: 9041645
  173. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.
    Neurology. 1996 Nov;47(5):1113-24 PMID: 8909416
  174. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
    Neurology. 1984 Jul;34(7):939-44 PMID: 6610841
  175. The aggregation and fibrillation of alpha-synuclein.
    Acc Chem Res. 2006 Sep;39(9):628-34 PMID: 16981679
  176. Methionine oxidation, alpha-synuclein and Parkinson's disease.
    Biochim Biophys Acta. 2005 Jan 17;1703(2):157-69 PMID: 15680224
  177. Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein.
    Neurology. 1998 Sep;51(3):887-9 PMID: 9748051
  178. Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form.
    J Biol Chem. 2002 Jan 4;277(1):671-8 PMID: 11679584
  179. The influence of macromolecular crowding and macromolecular confinement on biochemical reactions in physiological media.
    J Biol Chem. 2001 Apr 6;276(14):10577-80 PMID: 11279227
  180. Pesticides directly accelerate the rate of alpha-synuclein fibril formation: a possible factor in Parkinson's disease.
    FEBS Lett. 2001 Jul 6;500(3):105-8 PMID: 11445065
  181. Neuroaxonal dystrophy combined with diffuse Lewy body disease in a young adult.
    Clin Neuropathol. 1993 May-Jun;12(3):147-52 PMID: 8391956
  182. Calcium(II) selectively induces alpha-synuclein annular oligomers via interaction with the C-terminal domain.
    Protein Sci. 2004 Dec;13(12):3245-52 PMID: 15537754
  183. Natively unfolded human prothymosin alpha adopts partially folded collapsed conformation at acidic pH.
    Biochemistry. 1999 Nov 9;38(45):15009-16 PMID: 10555983
  184. Parkinson's disease and other alpha-synucleinopathies.
    Clin Chem Lab Med. 2001 Apr;39(4):308-12 PMID: 11388653
  185. The role of environmental toxins in the etiology of Parkinson's disease.
    Trends Neurosci. 1989 Feb;12(2):49-54 PMID: 2469210
  186. A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders.
    J Biomol Struct Dyn. 2003 Oct;21(2):211-34 PMID: 12956606
  187. Anti-HIV activity of medicinal herbs: usage and potential development.
    Am J Chin Med. 2001;29(1):69-81 PMID: 11321482
  188. Structural characterization of the molten globule and native states of apomyoglobin by solution X-ray scattering.
    J Mol Biol. 1995 May 26;249(1):215-28 PMID: 7776373
  189. Alpha-synuclein and the Lewy body disorders.
    Curr Opin Neurol. 2001 Aug;14(4):423-32 PMID: 11470957
  190. Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species.
    Arch Biochem Biophys. 1998 Aug 1;356(1):1-11 PMID: 9681984
  191. Alpha-synuclein misfolding and neurodegenerative diseases.
    Curr Protein Pept Sci. 2008 Oct;9(5):507-40 PMID: 18855701
  192. The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein.
    J Mol Biol. 2006 Mar 3;356(4):1036-48 PMID: 16403519
  193. Residual structure, backbone dynamics, and interactions within the synuclein family.
    J Mol Biol. 2007 Sep 21;372(3):689-707 PMID: 17681534
  194. Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein.
    Biochemistry. 2001 Sep 25;40(38):11604-13 PMID: 11560511
  195. Pathogenic effects of alpha-synuclein aggregation.
    Brain Res Mol Brain Res. 2005 Mar 24;134(1):3-17 PMID: 15790525
  196. Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling.
    Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8331-6 PMID: 15155902
  197. Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration.
    Protein Pept Lett. 2004 Jun;11(3):213-28 PMID: 15182223
  198. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.
    Nat Med. 1998 Nov;4(11):1318-20 PMID: 9809558
  199. Biological selectivity and functional aspects of protein tyrosine nitration.
    Biochem Biophys Res Commun. 2003 Jun 6;305(3):776-83 PMID: 12763060
  200. Contribution of somal Lewy bodies to neuronal death.
    Brain Res. 1997 Nov 14;775(1-2):24-9 PMID: 9439824
  201. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded.
    Biochemistry. 1996 Oct 29;35(43):13709-15 PMID: 8901511
  202. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal.
    J Neurosci. 1988 Aug;8(8):2804-15 PMID: 3411354
  203. Risk of dementia in Parkinson's disease: a community-based, prospective study.
    Neurology. 2001 Mar 27;56(6):730-6 PMID: 11274306
  204. Why are "natively unfolded" proteins unstructured under physiologic conditions?
    Proteins. 2000 Nov 15;41(3):415-27 PMID: 11025552
  205. Convergent pathobiologic model of Parkinson's disease.
    Ann N Y Acad Sci. 2003 Jun;991:152-66 PMID: 12846984
  206. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes.
    J Biol Chem. 1998 Apr 17;273(16):9443-9 PMID: 9545270
  207. Dementia in Parkinson's disease: cause and treatment.
    Curr Opin Neurol. 2004 Aug;17(4):399-404 PMID: 15247534
  208. Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation.
    J Biol Chem. 2005 Sep 2;280(35):30649-52 PMID: 16020550
  209. Decreased beta-amyloid and increased abnormal Tau deposition in the brain of aged patients with leprosy.
    Am J Pathol. 1994 Oct;145(4):771-5 PMID: 7943169
  210. Oxidative damage to proteins, lipids, and DNA in cortical brain regions from patients with dementia with Lewy bodies.
    J Neurochem. 1998 Jul;71(1):302-12 PMID: 9648879
  211. Prevalence of movement disorders in elderly community residents.
    Neuroepidemiology. 1994;13(4):175-8 PMID: 8090259
  212. A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins.
    J Mol Biol. 2003 Jun 13;329(4):763-78 PMID: 12787676
  213. Conformational behavior and aggregation of alpha-synuclein in organic solvents: modeling the effects of membranes.
    Biochemistry. 2003 Mar 11;42(9):2720-30 PMID: 12614167
  214. Alpha-synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson's disease.
    J Neurochem. 2003 Jun;85(6):1468-79 PMID: 12787066
  215. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease.
    Trends Neurosci. 1998 Jun;21(6):249-54 PMID: 9641537
  216. Rifampicin inhibits the toxicity of pre-aggregated amyloid peptides by binding to peptide fibrils and preventing amyloid-cell interaction.
    Biochem J. 1997 Mar 15;322 ( Pt 3):859-65 PMID: 9148761
  217. Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1430-5 PMID: 15671169
  218. Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils.
    J Mol Biol. 2002 Oct 4;322(5):1089-102 PMID: 12367530
  219. Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation.
    J Biol Chem. 2007 Feb 23;282(8):5862-70 PMID: 17189262
  220. Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from alpha-synuclein in vitro.
    Biochemistry. 2002 Feb 5;41(5):1502-11 PMID: 11814343
  221. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein.
    J Biol Chem. 2002 Feb 22;277(8):6344-52 PMID: 11744721
  222. Structural characteristics of alpha-synuclein oligomers stabilized by the flavonoid baicalein.
    J Mol Biol. 2008 Oct 31;383(1):214-23 PMID: 18775438
  223. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease.
    Ann Neurol. 2002 Sep;52(3):276-84 PMID: 12205639
  224. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies.
    Neurosci Lett. 1998 Jul 31;251(3):205-8 PMID: 9726379
  225. Antibodies to alpha-synuclein detect Lewy bodies in many Down's syndrome brains with Alzheimer's disease.
    Ann Neurol. 1999 Mar;45(3):353-7 PMID: 10072050
  226. Rifampicin inhibits alpha-synuclein fibrillation and disaggregates fibrils.
    Chem Biol. 2004 Nov;11(11):1513-21 PMID: 15556002
  227. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation.
    J Neurochem. 2007 Oct;103(1):17-37 PMID: 17623039
  228. Parkinsonism induced by solvent abuse.
    Ann Neurol. 1994 May;35(5):616-9 PMID: 8179306
  229. Neurodegenerative disease: amyloid pores from pathogenic mutations.
    Nature. 2002 Jul 18;418(6895):291 PMID: 12124613
  230. The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans.
    J Neurol Neurosurg Psychiatry. 1960 Nov;23:283-90 PMID: 13711997
  231. Accelerated oligomerization by Parkinson's disease linked alpha-synuclein mutants.
    Ann N Y Acad Sci. 2000;920:42-5 PMID: 11193175
  232. Lipid rafts, protein scaffolds, and neurologic disease.
    Neurology. 2007 Oct 16;69(16):1635-9 PMID: 17938374
  233. The ALS/PDC syndrome of Guam and the cycad hypothesis.
    Neurology. 2008 May 20;70(21):1984-90 PMID: 18490618
  234. Natively unfolded proteins: a point where biology waits for physics.
    Protein Sci. 2002 Apr;11(4):739-56 PMID: 11910019
  235. Oxidative stress and motor neurone disease.
    Brain Pathol. 1999 Jan;9(1):165-86 PMID: 9989458
  236. Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli.
    J Biol Chem. 2000 Aug 4;275(31):24065-9 PMID: 10818098
  237. Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.
    J Am Chem Soc. 2005 Jan 19;127(2):476-7 PMID: 15643843
  238. Chronic systemic pesticide exposure reproduces features of Parkinson's disease.
    Nat Neurosci. 2000 Dec;3(12):1301-6 PMID: 11100151
  239. Parkinson's disease and related alpha-synucleinopathies are brain amyloidoses.
    Ann N Y Acad Sci. 2003 Jun;991:107-10 PMID: 12846979
  240. Smoking and Parkinson's disease: does nicotine affect alpha-synuclein fibrillation?
    Biochim Biophys Acta. 2009 Feb;1794(2):282-90 PMID: 19013262
  241. Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go?
    Cell Mol Life Sci. 2003 Sep;60(9):1852-71 PMID: 14523548
  242. Etiology and pathogenesis of Parkinson's disease.
    Annu Rev Neurosci. 1999;22:123-44 PMID: 10202534
  243. Synucleins in synaptic plasticity and neurodegenerative disorders.
    J Neurosci Res. 1999 Oct 1;58(1):120-9 PMID: 10491577
  244. Smoking, nicotine and Parkinson's disease.
    Trends Neurosci. 2004 Sep;27(9):561-8 PMID: 15331239
  245. A Drosophila model of Parkinson's disease.
    Nature. 2000 Mar 23;404(6776):394-8 PMID: 10746727
Article Info
Journal
Current protein & peptide science
Abbr.
Curr Protein Pept Sci
ISSN
1875-5550
DOI
10.2174/138920309789351921
Email
vuversky@iupui.edu
Published
2009-10-00
Pages
483-99
Language
English
Region
United Arab Emirates
NLM ID
100960529
PMCID
PMC3786709
Subset
IM
Grants
NIA NIH HHS · R01 AG019391 · United States
NLM NIH HHS · R01 LM007688 · United States
NIA NIH HHS · R37 AG019391 · United States
NIA NIH HHS · R01 AG025440-04 · United States
NIA NIH HHS · R01 AG019391-09 · United States
NIA NIH HHS · R01 AG025440 · United States
NIGMS NIH HHS · R01 GM071714 · United States
NLM NIH HHS · R56 LM007688 · United States
External Links
PubMed source DOI: 10.2174/138920309789351921 PMC Full Text View journal details
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