Parkinson-Syndrom(e) – Neue Konzepte für eine sich ausbreitende Erkrankung?

J. Klucken; B. Herting; R. Hilker; J. B. Schulz; P. Vieregge; D. Woitalla; M. Wolz; H. Reichmann

doi:10.1055/s-0033-1349432

Aktuelle Neurologie, Table of Contents

Aktuelle Neurologie 2013; 40(06): 327-332
DOI: 10.1055/s-0033-1349432

Workshop

Parkinson-Syndrom(e) – Neue Konzepte für eine sich ausbreitende Erkrankung?

Parkinson Syndrome(s) – New Concepts for a Spreading Disease?

J. Klucken

¹Molekulare Neurologie, Universitätsklinikum Erlangen

,

B. Herting

²Klinik für Neurologie und Gerontoneurologie, Diakonie-Klinikum Schwäbisch Hall

,

R. Hilker

³Klinik für Neurologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt

,

J. B. Schulz

⁴Neurologische Klinik, Universitätsklinikum der RWTH Aachen

,

P. Vieregge

⁵Klinik für Neurologie, Klinikum Lippe-Lemgo GmbH

,

D. Woitalla

⁶Neurologische Klinik, Universitätsklinikum der Ruhr-Universität Bochum

,

M. Wolz

⁷Klinik für Neurologie, Elblandklinikum Meißen

,

H. Reichmann

⁸Klinik und Poliklinik für Neurologie, Carl Gustav Carus Universität Dresden

› Author Affiliations

Abstract

Zusammenfassung

Neueste Erkenntnisse über den klinischen Verlauf, die Pathologie und die zellbiologischen Konzepte der Parkinson-Syndrome legen eine kontinuierliche Ausbreitung sowohl von Symptomen als auch der zugrunde liegenden Schädigung des Nervensystems nahe. Diese Konzepte ändern den Blickwinkel, aus dem die Parkinson-Syndrome aus ärztlicher, neuropathologischer und zellbiologischer Sicht betrachtet werden. Dies hat Konsequenzen für die diagnostische Zuordnung und bietet neue therapeutische Optionen. In diesem Artikel werden diese neuen Sichtweisen zusammengefasst, und die entstehenden Kontroversen diskutiert. Der Ausblick veranschaulicht daraus resultierende erste Ansätze für neue therapeutische Strategien.

Abstract

The latest knowledge about the clinical course, pathology, and cell biological concepts in Parkinson’s disease suggest a continuous spreading of both the symptoms and the underlying degeneration of the nervous system. These new concepts influence the point-of-view of physicians, pathologists, and cell biologists: they have a substantial impact on the diagnostic classification and the development of novel therapeutic options. The present article outlines the new viewpoints and controversies, and summarises the resulting scientific concepts to develop therapeutic strategies.

Schlüsselwörter

Parkinson-Syndrome - Zell-zu-Zell-Propagation - Krankheitsverlauf

Keywords

Parkinson syndrome - cell-to-cell propagation - course of the disease

Full Text

References

Literatur
1 Oertel WH, Reichmann H. Parkinson-Syndrome: Diagnostik und Therapie. In: Diener HC, Putzki H, Hrsg. Leitlinien der Deutschen Gesellschaft für Neurologie. Stuttgart: Georg Thieme Verlag; 2008
2 Clarke G, Lumsden CJ, McInnes RR. Inherited neurodegenerative diseases: the one-hit model of neurodegeneration. Hum Mol Genet 2001; 10: 2269-2275
3 Fahn S. Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 2003; 991: 1-14
4 Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord 2011; 26: 1049-1055
5 Malkus KA, Tsika E, Ischiropoulos H. Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson’s disease: how neurons are lost in the Bermuda triangle. Mol Neurodegener 2009; 4: 24
6 Khoo TK, Yarnall AJ, Duncan GW et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology 2013; 80: 276-281
7 Riedel O, Heuser I, Klotsche J et al. Occurrence risk and structure of depression in Parkinson disease with and without dementia: results from the GEPAD Study. J Geriatr Psychiatry Neurol 2010; 23: 27-34
8 Zahodne LB, Marsiske M, Okun MS et al. Components of depression in Parkinson disease. J Geriatr Psychiatry Neurol 2012; 25: 131-137
9 Doty RL. Olfaction in Parkinson’s disease and related disorders. Neurobiol Dis 2012; 46: 527-552
10 Berardelli A, Wenning GK, Antonini A et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 2013; 20: 16-34
11 Shults CW. Lewy bodies. Proc Natl Acad Sci U S A 2006; 103: 1661-1668
12 Saito Y, Ruberu NN, Sawabe M et al. Lewy body-related alpha-synucleinopathy in aging. J Neuropathol Exp Neurol 2004; 63: 742-749
13 Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord 2003; 18 (Suppl. 06) S2-12
14 Goedert M, Spillantini MG. Lewy body diseases and multiple system atrophy as alpha-synucleinopathies. Mol Psychiatry 1998; 3: 462-465
15 Ferrer I. Neuropathology and neurochemistry of nonmotor symptoms in Parkinson’s disease. Parkinsons Dis 2011; 2011: 708404
16 Kupsky WJ, Grimes MM, Sweeting J et al. Parkinson’s disease and megacolon: concentric hyaline inclusions (Lewy bodies) in enteric ganglion cells. Neurology 1987; 37: 1253-1255
17 Wakabayashi K, Takahashi H. Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 1997; 38 (Suppl. 02) 2-7
18 Rajput AH, Rozdilsky B. Dysautonomia in Parkinsonism: a clinicopathological study. J Neurol Neurosurg Psychiatry 1976; 39: 1092-1100
19 Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol 2008; 15 (Suppl. 01) 14-20
20 Siderowf A, Lang AE. Premotor Parkinson’s disease: concepts and definitions. Mov Disord 2012; 27: 608-616
21 Noyce AJ, Bestwick JP, Silveira-Moriyama L et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 2012; 72: 893-901
22 Walter U, Klucken J, Benecke R et al. Brain Sonography, Olfactory and Motor Function Assessment for the Early Diagnosis of Idiopathic Parkinson’s Disease. Akt Neurol 2012; 39: 127-134
23 Winkler J, Ehret R, Buttner T et al. Parkinson’s disease risk score: moving to a premotor diagnosis. J Neurol 2011; 258 (Suppl. 02) S311-S315
24 Stiasny-Kolster K, Doerr Y, Moller JC et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005; 128: 126-137
25 Jost WH, Eckardt VF. Constipation in idiopathic Parkinson’s disease. Scand J Gastroenterol 2003; 38: 681-686
26 Reichmann H. View point: etiology in Parkinson’s disease. Dual hit or spreading intoxication. J Neurol Sci 2011; 310: 9-11
27 Del Tredici K, Braak H. Lewy pathology and neurodegeneration in premotor Parkinson’s disease. Mov Disord 2012; 27: 597-607
28 Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology 1995; 45: 669-671
29 Poewe WH, Wenning GK. The natural history of Parkinson’s disease. Neurology 1996; 47 (Suppl. 03) S146-S152
30 Hely MA, Morris JG, Reid WG et al. Age at onset: the major determinant of outcome in Parkinson’s disease. Acta Neurol Scand 1995; 92: 455-463
31 Doty RL, Golbe LI, McKeown DA et al. Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson’s disease. Neurology 1993; 43: 962-965
32 Puschmann A. Monogenic Parkinson’s disease and parkinsonism: Clinical phenotypes and frequencies of known mutations. Parkinsonism Relat Disord 2013; 19: 407-415
33 Gasser T, Hardy J, Mizuno Y. Milestones in PD genetics. Mov Disord 2011; 26: 1042-1048
34 Gomez Arevalo G, Jorge R, Garcia S et al. Clinical and pharmacological differences in early- versus late-onset Parkinson’s disease. Mov Disord 1997; 12: 277-284
35 Kostic V, Przedborski S, Flaster E et al. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 1991; 41: 202-205
36 Wickremaratchi MM, Knipe MD, Sastry BS et al. The motor phenotype of Parkinson’s disease in relation to age at onset. Mov Disord 2011; 26: 457-463
37 Healy DG, Falchi M, O’Sullivan SS et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008; 7: 583-590
38 Kagi G, Klein C, Wood NW et al. Nonmotor symptoms in Parkin gene-related parkinsonism. Mov Disord 2010; 25: 1279-1284
39 Schrag A, Ben-Shlomo Y, Brown R et al. Young-onset Parkinson’s disease revisited – clinical features, natural history, and mortality. Mov Disord 1998; 13: 885-894
40 Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 2011; 91: 1161-1218
41 Lill CM, Roehr JT, McQueen MB et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: The PDGene database. PLoS Genet 2012; 8: e1002548
42 Xiang W, Schlachetzki JC, Bussmann J et al. Oxidative stress-induced posttranslational modifications of alpha-synuclein: Specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Mol Cell Neurosci 2013; 54: 71-83
43 Spillantini MG, Schmidt ML, Lee VM et al. Alpha-synuclein in Lewy bodies. Nature 1997; 388: 839-840
44 Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 1998; 4: 1318-1320
45 Klucken J, Ingelsson M, Shin Y et al. Clinical and biochemical correlates of insoluble alpha-synuclein in dementia with Lewy bodies. Acta Neuropathol 2006; 111: 101-108
46 Olanow CW, Perl DP, DeMartino GN et al. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 2004; 3: 496-503
47 Winner B, Jappelli R, Maji SK et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 2011; 108: 4194-4199
48 Klucken J, Poehler AM, Ebrahimi-Fakhari D et al. Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway. Autophagy 2012; 8: 754-766
49 Dunning CJ, George S, Brundin P. What’s to like about the prion-like hypothesis for the spreading of aggregated alpha-synuclein in Parkinson disease?. Prion 2013; 7: 92-97
50 El-Agnaf OM, Salem SA, Paleologou KE et al. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. Faseb J 2006; 20: 419-425
51 Braak H, Bohl JR, Muller CM et al. Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 2006; 21: 2042-2051
52 Braak H, Del Tredici K, Rub U et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24: 197-211
53 Shannon KM, Keshavarzian A, Mutlu E et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord 2012; 27: 709-715
54 Braak H, de Vos RA, Bohl J et al. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 2006; 396: 67-72
55 Kalaitzakis ME, Graeber MB, Gentleman SM et al. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of alpha-synuclein staging. Neuropathol Appl Neurobiol 2008; 34: 284-295
56 Halliday G, Lees A, Stern M. Milestones in Parkinson’s disease – clinical and pathologic features. Mov Disord 2011; 26: 1015-1021
57 Burke RE, Dauer WT, Vonsattel JP. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 2008; 64: 485-491
58 Burke RE, O’Malley K. Axon degeneration in Parkinson’s disease. Exp Neurol 2012; 246: 72-83
59 Selikhova M, Williams DR, Kempster PA et al. A clinico-pathological study of subtypes in Parkinson’s disease. Brain 2009; 132: 2947-2957
60 Parkkinen L, Kauppinen T, Pirttila T et al. Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 2005; 57: 82-91
61 Jellinger KA. Formation and development of Lewy pathology: a critical update. J Neurol 2009; 256 (Suppl. 03) 270-279
62 Parkkinen L, Silveira-Moriyama L, Holton JL et al. Can olfactory bulb biopsy be justified for the diagnosis of Parkinson’s disease? Comments on “olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders”. Acta Neuropathol 2009; 117: 213-214; author reply 217 – 218
63 Parkkinen L, Pirttila T, Alafuzoff I. Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 2008; 115: 399-407
64 Beach TG, Adler CH, Sue LI et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 2010; 119: 689-702
65 Alafuzoff I, Ince PG, Arzberger T et al. Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 2009; 117: 635-652
66 Li JY, Englund E, Holton JL et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 2008; 14: 501-503
67 Kordower JH, Chu Y, Hauser RA et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008; 14: 504-506
68 Brundin P, Li JY, Holton JL et al. Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 2008; 9: 741-745
69 El-Agnaf OM, Salem SA, Paleologo KE et al. Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 2003; 17: 1945-1947
70 Emmanouilidou E, Melachroinou K, Roumeliotis T et al. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010; 30: 6838-6851
71 Freundt EC, Maynard N, Clancy EK et al. Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. Ann Neurol 2012; 72: 517-524
72 Alvarez-Erviti L, Seow Y, Schapira AH et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 2011; 42: 360-367
73 Hansen C, Angot E, Bergstrom AL et al. Alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 2011; 121: 715-725
74 Lee HJ, Suk JE, Bae EJ et al. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 2008; 40: 1835-1849
75 Danzer KM, Ruf WP, Putcha P et al. Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. Faseb J 2011; 25: 326-336
76 Desplats P, Lee HJ, Bae EJ et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 2009; 106: 13010-13015
77 Diogenes MJ, Dias RB, Rombo DM et al. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci 2012; 32: 11750-11762
78 Hilker R, Brotchie JM, Chapman J. Pros and cons of a prion-like pathogenesis in Parkinson’s disease. BMC Neurol 2011; 11: 74
79 Luk KC, Song C, O’Brien P et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A 2009; 106: 20051-20056
80 Steiner JA, Angot E, Brundin P. A deadly spread: cellular mechanisms of alpha-synuclein transfer. Cell Death Differ 2011; 18: 1425-1433
81 Luk KC, Kehm V, Carroll J et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012; 338: 949-953
82 Luk KC, Kehm VM, Zhang B et al. Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med 2012; 209: 975-986
83 Pan-Montojo F, Anichtchik O, Dening Y et al. Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 2010; 5: e8762
84 Pan-Montojo F, Schwarz M, Winkler C et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2012; 2: 898
85 Mollenhauer B, Locascio JJ, Schulz-Schaeffer W et al. alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 2011; 10: 230-240
86 Lee PH, Lee G, Park HJ et al. The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. J Neural Transm 2006; 113: 1435-1439
87 Lebouvier T, Coron E, Chaumette T et al. Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol Motil 2010; 22: e11-14
88 Postuma RB, Aarsland D, Barone P et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord 2012; 27: 617-626
89 Meusel T, Westermann B, Fuhr P et al. The course of olfactory deficits in patients with Parkinson’s disease – a study based on psychophysical and electrophysiological measures. Neurosci Lett 2010; 486: 166-170
90 Haehner A, Hummel T, Reichmann H. Olfactory dysfunction as a diagnostic marker for Parkinson’s disease. Expert Rev Neurother 2009; 9: 1773-1779
91 Behnke S, Schroder U, Berg D. Transcranial sonography in the premotor diagnosis of Parkinson’s disease. Int Rev Neurobiol 2010; 90: 93-106
92 van de Loo S, Walter U, Behnke S et al. Reproducibility and diagnostic accuracy of substantia nigra sonography for the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 2010; 81: 1087-1092
93 Masliah E, Rockenstein E, Adame A et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 2005; 46: 857-868
94 Reynolds AD, Stone DK, Hutter JA et al. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol 2010; 184: 2261-2271
95 Bae EJ, Lee HJ, Rockenstein E et al. Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J Neurosci 2012; 32: 13454-13469
96 Masliah E, Rockenstein E, Mante M et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 2011; 6: e19338