Übergreifende Konzepte der Neurodegeneration

Zusammenfassung

Nach jahrzehntelanger Suche nach den molekularen Grundlagen der Neurodegeneration, die zahllose mögliche aber dann wieder verworfene oder als Epiphänomene eingeordnete Mechanismen aufgedeckt haben, kristallisiert sich ein möglicherweise gemeinsames und übergreifendes Konzept der Ausbreitung neurodegenerativer Erkrankungen heraus. Dieses Prinzip der prionartigen Ausbreitung der Synucleinopathien, Tauopathien und β-Amyloiderkrankungen wird hier dargestellt. Dieses Konzept ist noch nicht ausgereift und ausreichend belegt, aber es ist wert auch von Klinikern zur Kenntnis genommen zu werden. Neue Wege der Therapieforschung können damit eingeschlagen werden.

Abstract

Over many years of extensive research on the molecular principles of neurodegeneration, numerous different hypotheses were suggested and rejected; now a common and overlapping concept of neurodegeneration appears to have crytallised. This is the concept of prion-like spreading in alpha-synucleinopathies, tauopathies and beta-amyloid diseases and is highlighted in this review. Despite the concept being far from being proven, clinicians should take notice of these developments. This new hypothesis may encourage new therapeutic approaches for neurodegenerative disorders.

Schlüsselwörter

Neurodegeneration - prionartige Erkrankungen - Synucleinopathien - Tauopathien

Keywords

prion-like disease - neurodegeneration - synucleinopathy - tauopathy

• Literatur

• 1 Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013; 501: 45-51
• 2 Forloni G, Artuso V, La Vitola P. et al. Oligomeropathies and pathogenesis of Alzheimer and Parkinson‘s diseases. Mov Disord 2016; 31: 771-781
• 3 Witt K, Deuschl G, Bartsch T. Frontotemporal dementias. Der Nervenarzt 2013; 84: 20-32
• 4 Mayo MC, Bordelon Y. Dementia with Lewy bodies. Seminars in neurology 2014; 34: 182-188
• 5 Thal DR, Rub U, Orantes M. et al. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58: 1791-1800
• 6 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
• 7 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239-259
• 8 Goedert M. Neurodegeneration. Alzheimer‘s and Parkinson‘s diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 2015; 349: 1255555
• 9 Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998; 95: 13363-13383
• 10 Aguzzi A, Lakkaraju AK. Cell Biology of Prions and Prionoids: A Status Report. Trends Cell Biol 2016; 26: 40-51
• 11 Vilchez D, Saez I, Dillin A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun 2014; 5: 5659
• 12 Wadsworth JD, Collinge J. Molecular pathology of human prion disease. Acta neuropathologica 2011; 121: 69-77
• 13 Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science 2007; 318: 930-936
• 14 Kahle PJ, Neumann M, Ozmen L. et al. Subcellular localization of wild-type and Parkinson‘s disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J Neurosci 2000; 20: 6365-6373
• 15 Singleton AB, Farrer M, Johnson J. et al. alpha-Synuclein locus triplication causes Parkinson‘s disease. Science 2003; 302: 841
• 16 Hardy J. Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochem Soc Trans 2005; 33: 578-581
• 17 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
• 18 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
• 19 Chu Y, Kordower JH. Lewy body pathology in fetal grafts. Ann N Y Acad Sci 2010; 1184: 55-67
• 20 Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 2005; 25: 6016-6024
• 21 Volpicelli-Daley LA, Luk KC, Patel TP. et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011; 72: 57-71
• 22 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
• 23 Angot E, Steiner JA, Lema Tome CM. et al. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 2012; 7: e39465
• 24 Mougenot AL, Nicot S, Bencsik A. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 2012; 33: 2225-2228
• 25 Recasens A, Dehay B, Bove J. et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014; 75: 351-362
• 26 Paumier KL, Luk KC, Manfredsson FP. et al. Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 2015; 82: 185-199
• 27 Prusiner SB, Woerman AL, Mordes DA. et al. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A 2015; 112: E5308-E5317
• 28 Peelaerts W, Bousset L, Van der Perren A. et al. alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 2015; 522: 340-344
• 29 Melki R. Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases. J Parkinsons Dis 2015; 5: 217-227
• 30 Del Tredici K, Braak H. Review: Sporadic Parkinson‘s disease: development and distribution of alpha-synuclein pathology. Neuropathol Appl Neurobiol 2016; 42: 33-50
• 31 Bruni AC, Conidi ME, Bernardi L. Genetics in degenerative dementia: current status and applicability. Alzheimer Dis Assoc Disord 2014; 28: 199-205
• 32 Ridley RM, Baker HF, Windle CP. et al. Very long term studies of the seeding of beta-amyloidosis in primates. J Neural Transm (Vienna) 2006; 113: 1243-1251
• 33 Meyer-Luehmann M, Coomaraswamy J, Bolmont T. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 2006; 313: 1781-1784
• 34 Eisele YS, Obermuller U, Heilbronner G. et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 2010; 330: 980-982
• 35 Eisele YS, Bolmont T, Heikenwalder M. et al. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A 2009; 106: 12926-12931
• 36 Morales R, Duran-Aniotz C, Castilla J. et al. De novo induction of amyloid-beta deposition in vivo. Mol Psychiatry 2012; 17: 1347-1353
• 37 Stohr J, Condello C, Watts JC. et al. Distinct synthetic Abeta prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci U S A 2014; 111: 10329-10334
• 38 Cohen ML, Kim C, Haldiman T. et al. Rapidly progressive Alzheimer‘s disease features distinct structures of amyloid-beta. Brain 2015; 138: 1009-1022
• 39 Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001; 24: 1121-1159
• 40 Walker LC, Jucker M. Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci 2015; 38: 87-103
• 41 Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propagation of aggregated tau and alpha-synuclein in neurodegeneration. Brain 2017; 140: 266-278
• 42 Nonaka T, Watanabe ST, Iwatsubo T. et al. Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases. J Biol Chem 2010; 285: 34885-34898
• 43 Falcon B, Cavallini A, Angers R. et al. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem 2015; 290: 1049-1065
• 44 Clavaguera F, Bolmont T, Crowther RA. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009; 11: 909-913
• 45 de Calignon A, Polydoro M, Suarez-Calvet M. et al. Propagation of tau pathology in a model of early Alzheimer‘s disease. Neuron 2012; 73: 685-697
• 46 Clavaguera F, Akatsu H, Fraser G. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A 2013; 110: 9535-9540
• 47 Saito Y, Ruberu NN, Sawabe M. et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 2004; 63: 911-918
• 48 Grad LI, Fernando SM, Cashman NR. From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis. Neurobiol Dis 2015; 77: 257-265
• 49 Synofzik M, Ronchi D, Keskin I. et al. Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS. Hum Mol Genet 2012; 21: 3568-3574
• 50 Gurney ME, Pu H, Chiu AY. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994; 264: 1772-1775
• 51 Bendotti C, Marino M, Cheroni C. et al. Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Prog Neurobiol 2012; 97: 101-126
• 52 Grad LI, Guest WC, Yanai A. et al. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci U S A 2011; 108: 16398-16403
• 53 Graffmo KS, Forsberg K, Bergh J. et al. Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Hum Mol Genet 2013; 22: 51-60
• 54 Ayers JI, Fromholt S, Koch M. et al. Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol 2014; 128: 791-803
• 55 Neumann M, Sampathu DM, Kwong LK. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130-133
• 56 Lee S, Kim HJ. Prion-like mechanism in amyotrophic lateral sclerosis: are protein aggregates the key?. Exp Neurobiol 2015; 24: 1-7
• 57 Feiler MS, Strobel B, Freischmidt A. et al. TDP-43 is intercellularly transmitted across axon terminals. J Cell Biol 2015; 211: 897-911
• 58 Braak H, Brettschneider J, Ludolph AC. et al. Amyotrophic lateral sclerosis–a model of corticofugal axonal spread. Nat Rev Neurol 2013; 9: 708-714
• 59 Jaunmuktane Z, Mead S, Ellis M. et al. Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 2015; 525: 247-250
• 60 Frontzek K, Lutz MI, Aguzzi A. et al. Amyloid-beta pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly 2016; 146: w14287
• 61 Sevigny J, Chiao P, Bussiere T. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer‘s disease. Nature 2016; 537: 50-56