Alpha-synuclein propagation: New insights from animal models
Corresponding Author
Benjamin Dehay PhD
Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
CNRS, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
Correspondence to: Dr. Benjamin Dehay Université de Bordeaux, Institut des Maladies Neurodégénératives, CNRS UMR 5293, 146 rue Léo Saignat, 33076 Bordeaux cedex, France. E-mail: [email protected]Search for more papers by this authorMiquel Vila MD, PhD
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, Barcelona, Spain
Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
Catalan Institution for Research and Advanced Studies, Barcelona, Spain
Search for more papers by this authorErwan Bezard PhD
Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
CNRS, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
Search for more papers by this authorPatrik Brundin PhD
Laboratory for Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA
Search for more papers by this authorJeffrey H. Kordower PhD
Department of Neurological Sciences, The Graduate College, Rush University, Chicago, Illinois, USA
Search for more papers by this authorCorresponding Author
Benjamin Dehay PhD
Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
CNRS, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
Correspondence to: Dr. Benjamin Dehay Université de Bordeaux, Institut des Maladies Neurodégénératives, CNRS UMR 5293, 146 rue Léo Saignat, 33076 Bordeaux cedex, France. E-mail: [email protected]Search for more papers by this authorMiquel Vila MD, PhD
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, Barcelona, Spain
Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
Catalan Institution for Research and Advanced Studies, Barcelona, Spain
Search for more papers by this authorErwan Bezard PhD
Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
CNRS, Institut des Maladies Neurodégénératives, UMR 5293 Bordeaux, France
Search for more papers by this authorPatrik Brundin PhD
Laboratory for Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA
Search for more papers by this authorJeffrey H. Kordower PhD
Department of Neurological Sciences, The Graduate College, Rush University, Chicago, Illinois, USA
Search for more papers by this authorFunding agencies: The University of Bordeaux and the Centre National de la Recherche Scientifique provided infrastructural support. This work was supported by Agence Nationale de la Recherche Grants ANR-12-BSV4-0001-01 and LABEX BRAIN ANR-10-LABX-43 (to E.B.) and Fondo de Investigación Sanitaria-Instituto de Salud Carlos III, Spain (to M.V.).
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online version of this article.
ABSTRACT
Aggregation of alpha-synuclein is implicated in several neurodegenerative diseases collectively termed synucleinopathies. Emerging evidence strongly implicates cell-to-cell transmission of misfolded alpha-synuclein as a common pathogenetic mechanism in synucleinopathies. The impact of alpha-synuclein pathology on neuronal dysfunction and behavioral impairments is being explored in animal models. This review provides an update on how research in animal models supports the concept that misfolded alpha-synuclein spreads from cell to cell and describes how findings in animal models might relate to the disease process in humans. Finally, we discuss the current underlying molecular and cellular mechanisms and future therapeutic strategies targeting alpha-synuclein propagation. © 2015 International Parkinson and Movement Disorder Society
References
- 1
Dehay B. Targeting α-synuclein for treating Parkinson's disease: mechanistic and therapeutic considerations. Lancet Neurol 2015; 14: 855-866.
- 2
Polymeropoulos MH,
Lavedan C,
Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045-2047.
- 3
Chartier-Harlin MC,
Kachergus J,
Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004; 364: 1167-1169.
- 4
Singleton AB,
Farrer M,
Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science 2003; 302: 841.
- 5
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.
- 6
Zarranz JJ,
Alegre J,
Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004; 55: 164-173.
- 7
Appel-Cresswell S,
Vilarino-Guell C,
Encarnacion M, et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord 2013; 28: 811-813.
- 8
Proukakis C,
Dudzik CG,
Brier T, et al. A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 2013; 80: 1062-1064.
- 9
Lesage S,
Anheim M,
Letournel F, et al. G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol 2013; 73: 459-471.
- 10
Pasanen P,
Myllykangas L,
Siitonen M, et al. Novel alpha-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiol Aging 2014; 35:2180 e2181-e2185.
- 11
Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord 2003; 18(Suppl 6): S2-S12.
- 12
Goedert M,
Spillantini MG,
Del Tredici K,
Braak H. 100 years of Lewy pathology. Nat Rev Neurol 2013; 9: 13-24.
- 13
Wakabayashi K,
Hayashi S,
Kakita A, et al. Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 1998; 96: 445-452.
- 14
Fernagut PO,
Dehay B,
Maillard A, et al. Multiple system atrophy: a prototypical synucleinopathy for disease-modifying therapeutic strategies. Neurobiol Dis 2014; 67: 133-139.
- 15
Recasens A,
Dehay B. Alpha-synuclein spreading in Parkinson's disease. Front Neuroanat 2014; 8: 159.
- 16
Braak H,
Del Tredici K,
Rub U,
de Vos RA,
Jansen Steur EN,
Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24: 197-211.
- 17
Hawkes CH,
Del Tredici K,
Braak H. Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 2007; 33: 599-614.
- 18
Kordower JH,
Chu Y,
Hauser RA,
Freeman TB,
Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 2008; 14: 504-506.
- 19
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.
- 20
Brundin P,
Li JY,
Holton JL,
Lindvall O,
Revesz T. Research in motion: the enigma of Parkinson's disease pathology spread. Nat Rev Neurosci 2008; 9: 741-745.
- 21
Magen I,
Chesselet MF. Genetic mouse models of Parkinson's disease: the state of the art. Prog Brain Res 2010; 184: 53-87.
- 22
Rockenstein E,
Mallory M,
Hashimoto M, et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 2002; 68: 568-578.
- 23
Westerlund M,
Ran C,
Borgkvist A, et al. Lrrk2 and alpha-synuclein are co-regulated in rodent striatum. Mol Cell Neurosci 2008; 39: 586-591.
- 24
Giasson BI,
Duda JE,
Quinn SM,
Zhang B,
Trojanowski JQ,
Lee VM. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002; 34: 521-533.
- 25
Emmer KL,
Waxman EA,
Covy JP,
Giasson BI. E46K human alpha-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment. J Biol Chem 2011; 286: 35104-35118.
- 26
Nuber S,
Harmuth F,
Kohl Z, et al. A progressive dopaminergic phenotype associated with neurotoxic conversion of alpha-synuclein in BAC-transgenic rats. Brain Neurol 2013; 136(Pt 2): 412-432.
- 27
Double KL,
Halliday GM. New face of neuromelanin. J Neural Transm Suppl 2006: 119-123.
- 28
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.
- 29
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.
- 30
Kordower JH,
Dodiya HB,
Kordower AM, et al. Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 2011; 43: 552-557.
- 31
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.
- 32
Reyes JF,
Rey NL,
Bousset L,
Melki R,
Brundin P,
Angot E. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 2014; 62: 387-398.
- 33
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.
- 34
Luk KC,
Kehm VM,
Zhang B,
O'Brien P,
Trojanowski JQ,
Lee VM. Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med 2012; 209: 975-986.
- 35
Luk KC,
Kehm V,
Carroll J, et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012; 338: 949-953.
- 36
Masuda-Suzukake M,
Nonaka T,
Hosokawa M, et al. Prion-like spreading of pathological alpha-synuclein in brain. Brain 2013; 136(Pt 4): 1128-1138.
- 37
Sacino AN,
Brooks M,
McGarvey NH, et al. Induction of CNS alpha-synuclein pathology by fibrillar and non-amyloidogenic recombinant alpha-synuclein. Acta Neuropathol Commun 2013; 1: 38.
- 38
Masuda-Suzukake M,
Nonaka T,
Hosokawa M, et al. Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol Commun 2014; 2: 88.
- 39
Paumier KL,
Luk KC,
Manfredsson FP, et al. Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 2015; 82: 185-199.
- 40
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.
- 41
Watts JC,
Giles K,
Oehler A, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A 2013; 110: 19555-19560.
- 42
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.
- 43
Bodner RA,
Outeiro TF,
Altmann S, et al. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A 2006; 103: 4246-4251.
- 44
Greffard S,
Verny M,
Bonnet AM,
Seilhean D,
Hauw JJ,
Duyckaerts C. A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol Aging 2010; 31: 99-103.
- 45
Osterberg VR,
Spinelli KJ,
Weston LJ,
Luk KC,
Woltjer RL,
Unni VK. Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism. Cell Rep 2015; 10: 1252-1260.
- 46
Ulusoy A,
Rusconi R,
Perez-Revuelta BI, et al. Caudo-rostral brain spreading of alpha-synuclein through vagal connections. EMBO Mol Med 2013; 5: 1051-1059.
- 47
Ulusoy A,
Musgrove RE,
Rusconi R, et al. Neuron-to-neuron alpha-synuclein propagation in vivo is independent of neuronal injury. Acta Neuropathol Commun 2015; 3: 13.
- 48
Rey NL,
Petit GH,
Bousset L,
Melki R,
Brundin P. Transfer of human alpha-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 2013; 126: 555-573.
- 49
Holmqvist S,
Chutna O,
Bousset L, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 2014; 128: 805-820.
- 50
Sacino AN,
Brooks M,
Thomas MA, et al. Intramuscular injection of alpha-synuclein induces CNS alpha-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci U S A 2014; 111: 10732-10737.
- 51
El-Agnaf OM,
Salem SA,
Paleologou 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.
- 52
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.
- 53
Jang A,
Lee HJ,
Suk JE,
Jung JW,
Kim KP,
Lee SJ. Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 2010; 113: 1263-1274.
- 54
Kunadt M,
Eckermann K,
Stuendl A, et al. Extracellular vesicle sorting of alpha-Synuclein is regulated by sumoylation. Acta Neuropathol 2015; 129: 695-713.
- 55
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.
- 56
Lee HJ,
Patel S,
Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 2005; 25: 6016-6024.
- 57
Danzer KM,
Kranich LR,
Ruf WP, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegen 2012; 7: 42.
- 58
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.
- 59
Gupta A,
Pulliam L. Exosomes as mediators of neuroinflammation. J Neuroinflamm 2014; 11: 68.
- 60
Lee HJ,
Suk JE,
Patrick C, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 2010; 285: 9262-9272.
- 61
Lee HJ,
Suk JE,
Bae EJ,
Lee JH,
Paik SR,
Lee SJ. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 2008; 40: 1835-1849.
- 62
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.
- 63
Kayed R,
Sokolov Y,
Edmonds B, et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 2004; 279: 46363-46366.
- 64
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.
- 65
Sato H,
Kato T,
Arawaka S. Potential of cellular and animal models based on a prion-like propagation of alpha-synuclein for assessing antiparkinson agents. Mol Neurobiol 2015; 52: 226-235.
- 66
Tran HT,
Chung CH,
Iba M, et al. A-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep 2014; 7: 2054-2065.
