Modulation of α-Synuclein Aggregation by Dopamine: A Review

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by (1) the selective loss of dopaminergic neurons in the substantia nigra and (2) the deposition of misfolded α-synuclein (α-syn) as amyloid fibrils in the intracellular Lewy bodies in various region of the brain. Current thinking suggests that an interaction between α-syn and dopamine (DA) leads to the selective death of neuronal cells and the accumulation of misfolded α-syn. However, the exact mechanism by which this occurs is not fully defined. DA oxidation could play a key role is the pathogenesis of PD by causing oxidative stress, mitochondria dysfunction and impairment of protein metabolism. Here, we review the literature on the role of DA and its oxidative intermediates in modulating the aggregation pathways of α-syn.

[1]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[2]  S. Bottomley,et al.  Formation of a high affinity lipid-binding intermediate during the early aggregation phase of alpha-synuclein. , 2008, Biochemistry.

[3]  D. Graham,et al.  Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. , 1978, Molecular pharmacology.

[4]  Patrik Brundin,et al.  Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. , 2002, Nature reviews. Neuroscience.

[5]  P. Axelsen,et al.  The E46K mutation in alpha-synuclein increases amyloid fibril formation. , 2005, The Journal of biological chemistry.

[6]  P. Lansbury,et al.  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. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Jun Hu,et al.  Inhibition of α‐synuclein fibrillization by dopamine analogs via reaction with the amino groups of α‐synuclein , 2005 .

[8]  M. Beal,et al.  Parkinson's disease. , 2007, Human molecular genetics.

[9]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[10]  H J Gundersen,et al.  The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[11]  A. Jonas,et al.  Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes* , 1998, The Journal of Biological Chemistry.

[12]  M. Citron,et al.  alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. , 1999, The Journal of biological chemistry.

[13]  Philippe Amouyel,et al.  α-synuclein locus duplication as a cause of familial Parkinson's disease , 2004, The Lancet.

[14]  V. Uversky,et al.  Stabilization of Partially Folded Conformation during α-Synuclein Oligomerization in Both Purified and Cytosolic Preparations* , 2001, The Journal of Biological Chemistry.

[15]  S. Bottomley,et al.  Dopamine promotes α‐synuclein aggregation into SDS‐resistant soluble oligomers via a distinct folding pathway , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  P. Lansbury,et al.  Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. , 2000, Biochemistry.

[17]  Armin Giese,et al.  Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding , 2007, The Journal of Neuroscience.

[18]  W. Burke,et al.  Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. , 2008, Acta neuropathologica.

[19]  V. Subramaniam,et al.  Dependence of alpha-synuclein aggregate morphology on solution conditions. , 2002, Journal of molecular biology.

[20]  Paul H. Axelsen,et al.  The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation* , 2005, Journal of Biological Chemistry.

[21]  D. Sulzer,et al.  Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. , 2000, Neuron.

[22]  L. Bubacco,et al.  Kinetic and Structural Analysis of the Early Oxidation Products of Dopamine , 2007, Journal of Biological Chemistry.

[23]  M G Spillantini,et al.  Alpha-synuclein in Lewy bodies. , 1997, Nature.

[24]  J. Trojanowski,et al.  Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations* , 2005, Journal of Biological Chemistry.

[25]  Peter T. Lansbury,et al.  Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct , 2001, Science.

[26]  R A Crowther,et al.  alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Lansbury,et al.  Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. , 2002, Biochemistry.

[28]  V. Uversky,et al.  Methionine oxidation inhibits fibrillation of human alpha-synuclein in vitro. , 2002, FEBS letters.

[29]  V. Uversky,et al.  Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. , 2001, The Journal of biological chemistry.

[30]  K. Vrana,et al.  Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase , 1998, Journal of neuroscience research.

[31]  Peter T. Lansbury,et al.  Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease , 1998, Nature Medicine.

[32]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[33]  W. G. Kelly,et al.  Functional genomic analysis of the ADP‐ribosylation factor family of GTPases: phylogeny among diverse eukaryotes and function in C. elegans , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  Reinhard Jahn,et al.  A Broken α-Helix in Folded α-Synuclein* , 2003, The Journal of Biological Chemistry.

[35]  Vladimir N Uversky,et al.  Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. , 2007, Journal of neurochemistry.

[36]  N. Voelcker,et al.  Annular alpha-synuclein oligomers are potentially toxic agents in alpha-synucleinopathy. Hypothesis , 2009, Neurotoxicity Research.

[37]  Hitoshi Takahashi,et al.  The Lewy body in Parkinson's disease: Molecules implicated in the formation and degradation of α‐synuclein aggregates , 2007, Neuropathology : official journal of the Japanese Society of Neuropathology.

[38]  Jie Li,et al.  Dopamine and L‐dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  P. Lansbury,et al.  Accelerated oligomerization by Parkinson's disease linked alpha-synuclein mutants. , 2000, Annals of the New York Academy of Sciences.

[40]  P. Lansbury,et al.  Accelerated Oligomerization by Parkinson's Disease Linked α‐Synuclein Mutants , 2000 .

[41]  V. Uversky,et al.  Methionine oxidation inhibits fibrillation of human α‐synuclein in vitro , 2002 .

[42]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[43]  A. Graybiel,et al.  Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease , 1988, Nature.

[44]  M. Caron,et al.  Molecular characterization of the dopamine transporter. , 1993, Trends in pharmacological sciences.

[45]  C. Masters,et al.  Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. , 1999, The American journal of pathology.

[46]  J. B. Justice,et al.  Reaction of oxidized dopamine with endogenous cysteine residues in the human dopamine transporter , 2001, Journal of neurochemistry.

[47]  D. Selkoe,et al.  Dopamine covalently modifies and functionally inactivates parkin , 2005, Nature Medicine.

[48]  Armin Giese,et al.  Different species of alpha-synuclein oligomers induce calcium influx and seeding. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[49]  D. Sulzer,et al.  Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics , 2003, Trends in Neurosciences.

[50]  Akira Nakashima,et al.  PHARMACOLOGY AND , 2006 .

[51]  Peter Riederer,et al.  The relevance of iron in the pathogenesis of Parkinson’s disease , 2011, Journal of neurochemistry.

[52]  J. Galvin Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson’s disease: a case for the selective vulnerability of the substantia nigra , 2006, Acta Neuropathologica.

[53]  V. Uversky,et al.  Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. , 2001, Biochemistry.

[54]  Vladimir N. Uversky,et al.  Neuropathology, biochemistry, and biophysics of α‐synuclein aggregation , 2007 .

[55]  Y. Lyubchenko,et al.  Effects of nitration on the structure and aggregation of α-synuclein , 2005 .

[56]  Y. Lyubchenko,et al.  Effects of nitration on the structure and aggregation of alpha-synuclein. , 2005, Brain research. Molecular brain research.

[57]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[58]  E. Masliah,et al.  Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[59]  P. Lansbury,et al.  Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. , 1997, Annual review of biochemistry.

[60]  P. Lansbury,et al.  Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. , 2002, Journal of molecular biology.

[61]  V. Uversky,et al.  Evidence for a Partially Folded Intermediate in α-Synuclein Fibril Formation* , 2001, The Journal of Biological Chemistry.

[62]  P. Lansbury,et al.  Dopamine affects the stability, hydration, and packing of protofibrils and fibrils of the wild type and variants of alpha-synuclein. , 2007, Biochemistry.

[63]  A. Hill,et al.  Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner. , 2009, Journal of molecular biology.

[64]  Fran Maher,et al.  Non-Aβ Component of Alzheimer's Disease Amyloid (NAC) Revisited: NAC and α-Synuclein Are Not Associated with Aβ Amyloid , 1999 .

[65]  V. Uversky,et al.  Role of individual methionines in the fibrillation of methionine-oxidized α-synuclein , 2004 .

[66]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[67]  P. Lansbury,et al.  Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alpha-synuclein. , 2000, Biochemistry.

[68]  V. Subramaniam,et al.  Dependence of α-synuclein aggregate morphology on solution conditions , 2002 .

[69]  L. Greene,et al.  Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[70]  M. Citron,et al.  Both Familial Parkinson’s Disease Mutations Accelerate α-Synuclein Aggregation* , 1999, The Journal of Biological Chemistry.

[71]  J Q Trojanowski,et al.  A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly* , 2001, The Journal of Biological Chemistry.

[72]  S. Gustincich,et al.  Inhibition of α-Synuclein Fibrillization by Dopamine Is Mediated by Interactions with Five C-Terminal Residues and with E83 in the NAC Region , 2008, PloS one.

[73]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[74]  D. Eliezer,et al.  Conformational properties of alpha-synuclein in its free and lipid-associated states. , 2001, Journal of molecular biology.

[75]  Sarah J. Tabrizi,et al.  Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity , 2000 .

[76]  A. Sidhu,et al.  Dopamine differentially induces aggregation of A53T mutant and wild type alpha-synuclein: insights into the protein chemistry of Parkinson's disease. , 2008, Biochemical and biophysical research communications.

[77]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[78]  W. Burke,et al.  3,4-Dihydroxyphenylacetaldehyde and hydrogen peroxide generate a hydroxyl radical: possible role in Parkinson's disease pathogenesis. , 2001, Brain research. Molecular brain research.

[79]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[80]  S. Tabrizi,et al.  Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. , 2000, Human molecular genetics.

[81]  V. Uversky,et al.  At low concentrations, 3,4-dihydroxyphenylacetic acid (DOPAC) binds non-covalently to alpha-synuclein and prevents its fibrillation. , 2009, Journal of molecular biology.

[82]  Kostas Vekrellis,et al.  Cell-produced α-synuclein oligomers are targeted to, and impair, the 26S proteasome , 2010, Neurobiology of Aging.

[83]  M. Zigmond,et al.  A role for alpha-synuclein in the regulation of dopamine biosynthesis. , 2002, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[84]  L. Bubacco,et al.  Kinetic and structural analysis of the early oxidation products of dopamine: analysis of the interactions with alpha-synuclein. , 2007, The Journal of biological chemistry.

[85]  M. Zigmond,et al.  A Role for α-Synuclein in the Regulation of Dopamine Biosynthesis , 2002, The Journal of Neuroscience.

[86]  V. Uversky,et al.  Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers. , 2003, FEBS letters.

[87]  Leonidas Stefanis,et al.  α-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis , 2006, The Journal of Neuroscience.

[88]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Heidi Phillips,et al.  Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System , 2000, Neuron.

[90]  V. Uversky,et al.  Nitration inhibits fibrillation of human α‐synuclein in vitro by formation of soluble oligomers , 2003 .

[91]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[92]  P. Lansbury,et al.  Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. , 2003, Annual review of neuroscience.

[93]  L. Elferink,et al.  Tyrosine Hydroxylase Is Inactivated by Catechol‐Quinones and Converted to a Redox‐Cycling Quinoprotein , 1999, Journal of neurochemistry.

[94]  C. Dobson,et al.  Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases , 2002, Nature.

[95]  H. Ischiropoulos,et al.  Cellular Oligomerization of α-Synuclein Is Determined by the Interaction of Oxidized Catechols with a C-terminal Sequence* , 2007, Journal of Biological Chemistry.

[96]  Jun Hu,et al.  Inhibition of α‐synuclein fibrillization by dopamine analogs via reaction with the amino groups of α‐synuclein , 2005 .

[97]  C. Masters,et al.  Formation of dopamine-mediated alpha-synuclein-soluble oligomers requires methionine oxidation. , 2009, Free radical biology & medicine.