Ursachen des idiopathischen Parkinson-Syndroms - Stand 2005

Zusammenfassung

Nach wie vor sind die Ursachen für die Entstehung eines idiopathischen Parkinson-Syndroms weitgehend unbekannt und Gegenstand intensiver Forschungsaktivitäten. Hinsichtlich der Erforschung der Pathogenese wurden in den letzten Jahren bedeutsame Fortschritte erzielt. So lieferten auch die seltenen hereditären Erkrankungen wertvolle Hinweise für die möglichen Pathogenesemechanismen bei den idiopathischen Fällen. In diesem kurzen Übersichtsartikel wird ein Überblick über die PARK-Gene gegeben und die ihnen bei Mutationen mutmaßlich zugrunde liegenden toxischen Auswirkungen eingegangen, soweit sie bekannt sind. Darüber hinaus werden weitere, für die Pathogenese bedeutsame Faktoren wie Umweltfaktoren, Entzündungsvorgänge, Proteasom, mitochondriale Dysfunktion, Eisentoxizität und Neuromelanin, Dopamin, Glutamat und Exzitotoxizität angesprochen. Außerdem wird auf die kontroverse Diskussion zum Absterbmechanismus der dopaminergen Neuronen (Apoptose versus Nekrose) eingegangen und schließlich der oxidative Stress als ein allen pathogenetischen Faktoren gemeinsames Bindeglied präsentiert.

Abstract

Intensive research activities are carried out to elucidate the causes underlying idiopathic Parkinson's disease. In recent years, significant progress has been achieved concerning the pathogenetic mechanisms and the hereditary cases have contributed valuable insights. This short review outlines the putative toxic mechanisms connected with mutations of the PARK genes, and summarizes other potentially important factors like environmental causes, inflammation, proteasome, mitochondrial dysfunction, iron toxicity and neuromelanin, dopamine, glutamate and excitotoxicity. The controversial discussion about the mechanism of dopaminergic cell death (apoptosis vs. necrosis) will be followed, and finally, oxidative stress will be presented as an intersecting common pathway of all pathogenetic factors.

Literatur

• 1 Fahn S, Sulzer D. Neurodegeneration and neuroprotection in Parkinson disease.  Neurorx. 2004;  1 139-154
• 2 Rijk M C de, Tzourio C, Breteler M M. et al . Prevalence of parkinsonism and Parkinson's disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson's disease.  J Neurol Neurosurg Psychiatry. 1997;  62 10-15
• 3 Priyadarshi A, Khuder S A, Schaub E A, Priyadarshi S S. Environmental risk factors and Parkinson's disease: a metaanalysis.  Environ Res. 2001;  86 122-127
• 4 Uversky V N. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration.  Cell Tissue Res. 2004;  318 225-241
• 5 Takahashi M, Yamada T, Nakajima S. et al . The substantia nigra is a major target for neurovirulent influenza A virus.  J Exp Med. 1995;  181 2161-2169
• 6 Carvey P M, Chang Q, Lipton J W, Ling Z. Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson's disease.  Front Biosci. 2003;  8 s826-s837
• 7 Ling Z, Chang Q A, Tong C W. et al . Rotenone potentiates dopamine neuron loss in animals exposed to lipopolysaccharide prenatally.  Exp Neurol. 2004;  190 373-383
• 8 Lannuzel A, Michel P P, Caparros-Lefebvre D. et al . Toxicity of Annonaceae for dopaminergic neurons: potential role in atypical parkinsonism in Guadeloupe.  Mov Disord. 2002;  17 84-90
• 9 Sherer T B, Betarbet R, Greenamyre J T. Pathogenesis of Parkinson's disease.  Curr Opin Investig Drugs. 2001;  2 657-662
• 10 Golbe L I. Alpha-synuclein and Parkinson's disease.  Adv Neurol. 2003;  91 165-174
• 11 Kruger R, Kuhn W, Muller T. et al . Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.  Nat Genet. 1998;  18 106-108
• 12 Zarranz J J, Alegre J, Gomez-Esteban J C. et al . The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.  Ann Neurol. 2004;  55 164-173
• 13 Conway K A, Rochet J C, Bieganski R M, Lansbury Jr P T. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct.  Science. 2001;  294 1346-1349
• 14 Maroteaux L, Campanelli J T, Scheller R H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal.  J Neurosci. 1988;  8 2804-2815
• 15 Clayton D F, George J M. Synucleins in synaptic plasticity and neurodegenerative disorders.  J Neurosci Res. 1999;  58 120-129
• 16 Sidhu A, Wersinger C, Vernier P. Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse?.  FASEB J. 2004;  18 637-647
• 17 Xu J, Kao S Y, Lee F J. et al . Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease.  Nat Med. 2002;  8 600-606
• 18 Volles M J, Lee S J, Rochet J C. et al . Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson's disease.  Biochemistry. 2001;  40 7812-7819
• 19 Sidhu A, Wersinger C, Vernier P. alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease.  FEBS Lett. 2004;  565 1-5
• 20 Snyder H, Wolozin B. Pathological proteins in Parkinson's disease: focus on the proteasome.  J Mol Neurosci. 2004;  24 425-442
• 21 Dawson T M, Dawson V L. Molecular pathways of neurodegeneration in Parkinson's disease.  Science. 2003;  302 819-822
• 22 Wersinger C, Banta M, Sidhu A. Comparative analyses of alpha-synuclein expression levels in rat brain tissues and transfected cells.  Neurosci Lett. 2004;  358 95-98
• 23 Chung K K, Zhang Y, Lim K L. et al . Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease.  Nat Med. 2001;  7 1144-1150
• 24 Corti O, Hampe C, Koutnikova H. et al . The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration.  Hum Mol Genet. 2003;  12 1427-1437
• 25 Engelender S, Kaminsky Z, Guo X. et al . Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions.  Nat Genet. 1999;  22 110-114
• 26 Palacino J J, Sagi D, Goldberg M S. et al . Mitochondrial dysfunction and oxidative damage in parkin-deficient mice.  J Biol Chem. 2004;  279 18614-18622
• 27 Chung K K, Thomas B, Li X. et al . S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function.  Science. 2004;  304 1328-1331
• 28 Jiang H, Ren Y, Zhao J, Feng J. Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis.  Hum Mol Genet. 2004;  13 1745-1754
• 29 Petrucelli L, O'Farrell C, Lockhart P J. et al . Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons.  Neuron. 2002;  36 1007-1019
• 30 Leroy E, Boyer R, Auburger G. et al . The ubiquitin pathway in Parkinson's disease.  Nature. 1998;  395 451-452
• 31 Osaka H, Wang Y L, Takada K. et al . Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron.  Hum Mol Genet. 2003;  12 1945-1958
• 32 Lowe J, McDermott H, Landon M. et al . Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases.  J Pathol. 1990;  161 153-160
• 33 Liu Y, Fallon L, Lashuel H A. et al . The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.  Cell. 2002;  111 209-218
• 34 Healy D G, Abou-Sleiman P M, Wood N W. PINK, PANK, or PARK? A clinicians' guide to familial parkinsonism.  Lancet Neurol. 2004;  3 652-662
• 35 Valente E M, Abou-Sleiman P M, Caputo V. et al . Hereditary early-onset Parkinson's disease caused by mutations in PINK1.  Science. 2004;  304 1158-1160
• 36 Bonifati V, Oostra B A, Heutink P. Unraveling the pathogenesis of Parkinson's disease - the contribution of monogenic forms.  Cell Mol Life Sci. 2004;  61 1729-1750
• 37 Bandopadhyay R, Kingsbury A E, Cookson M R. et al . The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease.  Brain. 2004;  127 420-430
• 38 Neumann M, Muller V, Gorner K. et al . Pathological properties of the Parkinson's disease-associated protein DJ-1 in alpha-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick's disease.  Acta Neuropathol (Berl). 2004;  107 489-496
• 39 Canet-Aviles R M, Wilson M A, Miller D W. et al . The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.  Proc Natl Acad Sci U S A. 2004;  101 9103-9108
• 40 Taira T, Saito Y, Niki T. et al . DJ-1 has a role in antioxidative stress to prevent cell death.  EMBO Rep. 2004;  5 213-218
• 41 Moore D J, Zhang L, Troncoso J. et al . Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress.  Hum Mol Genet. 2005;  14 71-84
• 42 Moore D J, West A B, Dawson V L, Dawson T M. Molecular Pathophysiology of Parkinson's Disease.  Annu Rev Neurosci. 2004;  28 55-84
• 43 Moore D J, Zhang L, Dawson T M, Dawson V L. A missense mutation (L166P) in DJ-1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo-oligomerization.  J Neurochem. 2003;  87 1558-1567
• 44 Miller D W, Ahmad R, Hague S. et al . L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system.  J Biol Chem. 2003;  278 36588-36595
• 45 Zimprich A, Biskup S, Leitner P. et al . Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.  Neuron. 2004;  44 601-607
• 46 Wszolek Z K, Pfeiffer R F, Tsuboi Y. et al . Autosomal dominant parkinsonism associated with variable synuclein and tau pathology.  Neurology. 2004;  62 1619-1622
• 47 Shen J. Protein kinases linked to the pathogenesis of Parkinson's disease.  Neuron. 2004;  44 575-577
• 48 Paisan-Ruiz C, Jain S, Evans E W. et al . Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.  Neuron. 2004;  44 595-600
• 49 Brice A. How much does dardarin contribute to Parkinson's disease?.  Lancet. 2005;  365 363-364
• 50 Fonzo A Di, Rohe C F, Ferreira J. et al . A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.  Lancet. 2005;  365 412-415
• 51 Gilks W P, Abou-Sleiman P M, Gandhi S. et al . A common LRRK2 mutation in idiopathic Parkinson's disease.  Lancet. 2005;  365 415-416
• 52 Nichols W C, Pankratz N, Hernandez D. et al . Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.  Lancet. 2005;  365 410-412
• 53 Walt J M van der, Noureddine M A, Kittappa R. et al . Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease.  Am J Hum Genet. 2004;  74 1121-1127
• 54 Le W D, Xu P, Jankovic J. et al . Mutations in NR4A2 associated with familial Parkinson disease.  Nat Genet. 2003;  33 85-89
• 55 McNaught K S, Olanow C W. Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson's disease.  Ann Neurol. 2003;  53, Suppl 3 S73-S84; discussion S84 - S86
• 56 Pickart C M, Cohen R E. Proteasomes and their kin: proteases in the machine age.  Nat Rev Mol Cell Biol. 2004;  5 177-187
• 57 Shringarpure R, Grune T, Mehlhase J, Davies K J. Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome.  J Biol Chem. 2003;  278 311-318
• 58 McNaught K S. Proteolytic dysfunction in neurodegenerative disorders.  Int Rev Neurobiol. 2004;  62 95-119
• 59 McNaught K S, Perl D P, Brownell A L, Olanow C W. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease.  Ann Neurol. 2004;  56 149-162
• 60 McNaught K S, Mytilineou C, Jnobaptiste R. et al . Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures.  J Neurochem. 2002;  81 301-306
• 61 Hoglinger G U, Carrard G, Michel P P. et al . Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease.  J Neurochem. 2003;  86 1297-1307
• 62 Kikuchi S, Shinpo K, Tsuji S. et al . Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons.  Brain Res. 2003;  964 228-236
• 63 Rockwell P, Yuan H, Magnusson R, Figueiredo-Pereira M E. Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2).  Arch Biochem Biophys. 2000;  374 325-333
• 64 Lindersson E, Beedholm R, Hojrup P. et al . Proteasomal inhibition by alpha-synuclein filaments and oligomers.  J Biol Chem. 2004;  279 12924-12934
• 65 Chen H, Zhang S M, Hernan M A. et al . Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease.  Arch Neurol. 2003;  60 1059-1064
• 66 Ouchi Y, Yoshikawa E, Sekine Y. et al . Microglial activation and dopamine terminal loss in early Parkinson's disease.  Ann Neurol. 2005;  57 168-175
• 67 Langston J W, Forno L S, Tetrud J. et al . Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure.  Ann Neurol. 1999;  46 598-605
• 68 Sherer T B, Betarbet R, Kim J H, Greenamyre J T. Selective microglial activation in the rat rotenone model of Parkinson's disease.  Neurosci Lett. 2003;  341 87-90
• 69 McGeer P L, McGeer E G. Inflammation and neurodegeneration in Parkinson's disease.  Parkinsonism Relat Disord. 2004;  10, Suppl 1 S3-S7
• 70 Herrera A J, Tomas-Camardiel M, Venero J L. et al . Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons.  J Neural Transm. 2005;  112 111-119
• 71 McGeer P L, Itagaki S, Boyes B E, McGeer E G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains.  Neurology. 1988;  38 1285-1291
• 72 Teismann P, Schulz J B. Cellular pathology of Parkinson's disease: astrocytes, microglia and inflammation.  Cell Tissue Res. 2004;  318 149-161
• 73 Giasson B I, Duda J E, Murray I V. et al . Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.  Science. 2000;  290 985-989
• 74 Hunot S, Hirsch E C. Neuroinflammatory processes in Parkinson's disease.  Ann Neurol. 2003;  53, Suppl 3 S49-S58; discussion S58 - S60
• 75 Sipos I, Tretter L, Adam-Vizi V. Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals.  J Neurochem. 2003;  84 112-118
• 76 Reichmann H, Riederer P. Biochemical analysis of respiratory chain enzymes in different brain regions of patients with Parkinson's disease. BMBFT Symposium „Morbus Parkinson und andere Basalganglienerkrankungen”. Bad Kissingen; 1989: S44
• 77 Lestienne P, Nelson J, Riederer P. et al . Normal mitochondrial genome in brain from patients with Parkinson's disease and complex I defect.  J Neurochem. 1990;  55 1810-1812
• 78 Mizuno Y, Ohta S, Tanaka M. et al . Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease.  Biochem Biophys Res Commun. 1989;  163 1450-1455
• 79 Schapira A H, Cooper J M, Dexter D. et al . Mitochondrial complex I deficiency in Parkinson's disease.  Lancet. 1989;  1 1269
• 80 Schapira A H, Cooper J M, Dexter D. et al . Mitochondrial complex I deficiency in Parkinson's disease.  J Neurochem. 1990;  54 823-827
• 81 Chinopoulos C, Adam-Vizi V. Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease.  J Neurochem. 2001;  76 302-306
• 82 Davey G P, Clark J B. Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria.  J Neurochem. 1996;  66 1617-1624
• 83 Davey G P, Peuchen S, Clark J B. Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration.  J Biol Chem. 1998;  273 12753-12757
• 84 Betarbet R, Sherer T B, MacKenzie G. et al . Chronic systemic pesticide exposure reproduces features of Parkinson's disease.  Nat Neurosci. 2000;  3 1301-1306
• 85 Scheffler I E. A century of mitochondrial research: achievements and perspectives.  Mitochondrion. 2001;  1 3-31
• 86 Dexter D T, Wells F R, Lees A J. et al . Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease.  J Neurochem. 1989;  52 1830-1836
• 87 Riederer P, Sofic E, Rausch W D. et al . Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains.  J Neurochem. 1989;  52 515-520
• 88 Behnke S, Berg D, Becker G. Does ultrasound disclose a vulnerability factor for Parkinson's disease?.  J Neurol. 2003;  250, Suppl 1 I24-I27
• 89 Berg D, Roggendorf W, Schroder U. et al . Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury.  Arch Neurol. 2002;  59 999-1005
• 90 Sommer U, Hummel T, Cormann K. et al . Detection of presymptomatic Parkinson's disease: combining smell tests, transcranial sonography, and SPECT.  Mov Disord. 2004;  19 1196-1202
• 91 Jellinger K, Paulus W, Grundke-Iqbal I. et al . Brain iron and ferritin in Parkinson's and Alzheimer's diseases.  J Neural Transm Park Dis Dement Sect. 1990;  2 327-340
• 92 Griffiths P D, Dobson B R, Jones G R, Clarke D T. Iron in the basal ganglia in Parkinson's disease. An in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy.  Brain. 1999;  122 667-673
• 93 Double K L, Maywald M, Schmittel M. et al . In vitro studies of ferritin iron release and neurotoxicity.  J Neurochem. 1998;  70 2492-2499
• 94 Tsai M J, Lee E H. Characterization of L-DOPA transport in cultured rat and mouse astrocytes.  J Neurosci Res. 1996;  43 490-495
• 95 Moos T. Absence of ferritin protein in substantia nigra pars compacta neurons. A reappraisal to the role of iron in Parkinson disease pathogenesis.  Mov Disord. 2000;  15 P 319 A
• 96 Zecca L, Tampellini D, Gatti A. et al . The neuromelanin of human substantia nigra and its interaction with metals.  J Neural Transm. 2002;  109 663-672
• 97 Zucca F A, Giaveri G, Gallorini M. et al . The neuromelanin of human substantia nigra: physiological and pathogenic aspects.  Pigment Cell Res. 2004;  17 610-617
• 98 Lopiano L, Chiesa M, Digilio G. et al . Q-band EPR investigations of neuromelanin in control and Parkinson's disease patients.  Biochim Biophys Acta. 2000;  1500 306-312
• 99 Kastner A, Hirsch E C, Lejeune O. et al . Is the vulnerability of neurons in the substantia nigra of patients with Parkinson's disease related to their neuromelanin content?.  J Neurochem. 1992;  59 1080-1089
• 100 Faucheux B A, Martin M E, Beaumont C. et al . Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease.  J Neurochem. 2003;  86 1142-1148
• 101 Ostrerova-Golts N, Petrucelli L, Hardy J. et al . The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity.  J Neurosci. 2000;  20 6048-6054
• 102 Uversky V N, Li J, Fink A L. 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;  276 44284-44296
• 103 Castellani R J, Siedlak S L, Perry G, Smith M A. Sequestration of iron by Lewy bodies in Parkinson's disease.  Acta Neuropathol (Berl). 2000;  100 111-114
• 104 Munch G, Luth H J, Wong A. et al . Crosslinking of alpha-synuclein by advanced glycation endproducts - an early pathophysiological step in Lewy body formation?.  J Chem Neuroanat. 2000;  20 253-257
• 105 Barcia C, Emborg M E, Hirsch E C, Herrero M T. Blood vessels and parkinsonism.  Front Biosci. 2004;  9 277-282
• 106 Kortekaas R, Leenders K L, van Oostrom J C. et al . Blood-brain barrier dysfunction in parkinsonian midbrain in vivo.  Ann Neurol. 2005;  57 176-179
• 107 Zhang F, Dryhurst G. Effects of L-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to idiopathic Parkinson's disease.  J Med Chem. 1994;  37 1084-1098
• 108 Spencer J P, Jenner P, Daniel S E. et al . Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species.  J Neurochem. 1998;  71 2112-2122
• 109 Zigmond M J, Hastings T G, Perez R G. Increased dopamine turnover after partial loss of dopaminergic neurons: compensation or toxicity?.  Parkinsonism Relat Disord. 2002;  8 389-393
• 110 Mogi M, Harada M, Kiuchi K. et al . Homospecific activity (activity per enzyme protein) of tyrosine hydroxylase increases in parkinsonian brain.  J Neural Transm. 1988;  72 77-82
• 111 Andrew R, Watson D G, Best S A. et al . The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls.  Neurochem Res. 1993;  18 1175-1177
• 112 Curtius H C, Wolfensberger M, Steinmann B. et al . Mass fragmentography of dopamine and 6-hydroxydopamine. Application to the determination of dopamine in human brain biopsies from the caudate nucleus.  J Chromatogr. 1974;  99 529-540
• 113 Dabbeni-Sala F, Santo S Di, Franceschini D. et al . Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity.  FASEB J. 2001;  15 164-170
• 114 Jones D C, Gunasekar P G, Borowitz J L, Isom G E. Dopamine-induced apoptosis is mediated by oxidative stress and Is enhanced by cyanide in differentiated PC12 cells.  J Neurochem. 2000;  74 2296-2304
• 115 Junn E, Mouradian M M. Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases.  J Neurochem. 2001;  78 374-383
• 116 Luo Y, Umegaki H, Wang X. et al . Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway.  J Biol Chem. 1998;  273 3756-3764
• 117 Offen D, Ziv I, Barzilai A. et al . Dopamine-melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease.  Neurochem Int. 1997;  31 207-216
• 118 Pedrosa R, Soares-da-Silva P. Oxidative and non-oxidative mechanisms of neuronal cell death and apoptosis by L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine.  Br J Pharmacol. 2002;  137 1305-1313
• 119 Rodriguez M C, Obeso J A, Olanow C W. Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection.  Ann Neurol. 1998;  44 S175-S188
• 120 Henneberry R C, Novelli A, Cox J A, Lysko P G. Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons. An hypothesis for cell death in aging and disease.  Ann N Y Acad Sci. 1989;  568 225-233
• 121 Olney J W, Sharpe L G. Brain lesions in an infant rhesus monkey treated with monsodium glutamate.  Science. 1969;  166 386-388
• 122 Blandini F, Porter R H, Greenamyre J T. Glutamate and Parkinson's disease.  Mol Neurobiol. 1996;  12 73-94
• 123 Richter C, Kass G E. Oxidative stress in mitochondria: its relationship to cellular Ca2+ homeostasis, cell death, proliferation, and differentiation.  Chem Biol Interact. 1991;  77 1-23
• 124 Gerlach M, Gsell W, Kornhuber J. et al . A post mortem study on neurochemical markers of dopaminergic, GABA-ergic and glutamatergic neurons in basal ganglia-thalamocortical circuits in Parkinson syndrome.  Brain Res. 1996;  741 142-152
• 125 Meoni P, Bunnemann B H, Kingsbury A E. et al . NMDA NR1 subunit mRNA and glutamate NMDA-sensitive binding are differentially affected in the striatum and pre-frontal cortex of Parkinson's disease patients.  Neuropharmacology. 1999;  38 625-633
• 126 Yamada T, McGeer P L, Baimbridge K G, McGeer E G. Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K.  Brain Res. 1990;  526 303-307
• 127 Mouatt-Prigent A, Agid Y, Hirsch E C. Does the calcium binding protein calretinin protect dopaminergic neurons against degeneration in Parkinson's disease?.  Brain Res. 1994;  668 62-70
• 128 Blum D, Torch S, Lambeng N. et al . Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease.  Prog Neurobiol. 2001;  65 135-172
• 129 Kerr J F, Wyllie A H, Currie A R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.  Br J Cancer. 1972;  26 239-257
• 130 Jellinger K A. Cell death mechanisms in Parkinson's disease.  J Neural Transm. 2000;  107 1-29
• 131 Yuan J, Yankner B A. Apoptosis in the nervous system.  Nature. 2000;  407 802-809
• 132 Shi Y. A structural view of mitochondria-mediated apoptosis.  Nat Struct Biol. 2001;  8 394-401
• 133 Syntichaki P, Tavernarakis N. The biochemistry of neuronal necrosis: rogue biology?.  Nat Rev Neurosci. 2003;  4 672-684
• 134 Kim J S, He L, Lemasters J J. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis.  Biochem Biophys Res Commun. 2003;  304 463-470
• 135 Mochizuki H, Mori H, Mizuno Y. Apoptosis in neurodegenerative disorders.  J Neural Transm Suppl. 1997;  50 125-140
• 136 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 25-31
• 137 Kosel S, Egensperger R, Eitzen U von. et al . On the question of apoptosis in the parkinsonian substantia nigra.  Acta Neuropathol (Berl). 1997;  93 105-108
• 138 Hartmann A, Hunot S, Michel P P. et al . Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease.  Proc Natl Acad Sci U S A. 2000;  97 2875-2880
• 139 Gerlach M, Reichmann H, Riederer P (Hrsg). Die Parkinson-Krankheit. 3., erweiterte und überarbeitete Auflage. Wien, New York; Springer Verlag 2003
• 140 Fahn S, Oakes D, Shoulson I. et al . Levodopa and the progression of Parkinson's disease.  N Engl J Med. 2004;  351 2498-2508
• 141 Buhmann C, Arlt S, Kontush A. et al . Plasma and CSF markers of oxidative stress are increased in Parkinson's disease and influenced by antiparkinsonian medication.  Neurobiol Dis. 2004;  15 160-170
• 142 Abraham S, Soundararajan C C, Vivekanandhan S, Behari M. Erythrocyte antioxidant enzymes in Parkinson's disease.  Indian J Med Res. 2005;  121 111-115
• 143 Feany M B. New genetic insights into Parkinson's disease.  N Engl J Med. 2004;  351 1937-1940
• 144 Frucht S J. Parkinson disease: an update.  Neurologist. 2004;  10 185-194