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Open Access 01-12-2015 | Research

Neuron-to-neuron α-synuclein propagation in vivo is independent of neuronal injury

Authors: Ayse Ulusoy, Ruth E Musgrove, Raffaella Rusconi, Michael Klinkenberg, Michael Helwig, Anja Schneider, Donato A Di Monte

Published in: Acta Neuropathologica Communications | Issue 1/2015

Abstract

Introduction

Interneuronal propagation of α-synuclein has been demonstrated in a variety of experimental models and may be involved in disease progression during the course of human synucleinopathies. The aim of this study was to assess the role that neuronal injury or, vice versa, cell integrity could have in facilitating interneuronal α-synuclein transfer and consequent protein spreading in an in vivo animal model.

Results

Viral vectors carrying the DNA for human α-synuclein were injected into the rat vagus nerve to trigger protein overexpression in the medulla oblongata and consequent spreading of human α-synuclein toward pons, midbrain and forebrain. Two vector preparations sharing the same viral construct were manufactured using identical procedures with the exception of methods for their purification. They were also injected at concentrations that induced comparable levels of α-synuclein transduction/overexpression in the medulla oblongata. α-Synuclein load was associated with damage (at 6 weeks post injection) and death (at 12 weeks) of medullary neurons after treatment with only one of the two vector preparations. Of note, neuronal injury and degeneration was accompanied by a substantial reduction of caudo-rostral propagation of human α-synuclein.

Conclusions

Interneuronal α-synuclein transfer, which underlies protein spreading from the medulla oblongata to more rostral brain regions in this rat model, is not a mere consequence of passive release from damaged or dead neurons. Neuronal injury and degeneration did not exacerbate α-synuclein propagation. In fact, data suggest that cell-to-cell passage of α-synuclein may be particularly efficient between intact, relatively healthy neurons.

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Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197–211, doi: S0197458002000659CrossRefPubMed

Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536, doi: 10.1007/s00702-002-0808-2CrossRefPubMed

Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc Natl Acad Sci U S A 106:13010–13015, doi:0903691106 10.1073/pnas.0903691106CrossRefPubMedCentralPubMed

Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P (2011) α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725, doi: 10.1172/JCI43366CrossRefPubMedCentralPubMed

Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VM (2012) Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 209:975–986, doi: 10.1084/jem.20112457CrossRefPubMedCentralPubMed

Freundt EC, Maynard N, Clancy EK, Roy S, Bousset L, Sourigues Y, Covert M, Melki R, Kirkegaard K, Brahic M (2012) Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport. Ann Neurol 72:517–524, doi: 10.1002/ana.23747CrossRefPubMedCentralPubMed

Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, Mann DM, Hasegawa M (2013) Prion-like spreading of pathological α-synuclein in brain. Brain 136:1128–1138, doi:awt037 10.1093/brain/awt037CrossRefPubMedCentralPubMed

Rey NL, Petit GH, Bousset L, Melki R, Brundin P (2013) Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 126:555–573, doi: 10.1007/s00401-013-1160-3CrossRefPubMedCentralPubMed

Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, Fernagut PO, Blesa J, Parent A, Perier C, Farinas I, Obeso JA, Bezard E, Vila M (2014) Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362, doi: 10.1002/ana.24066CrossRefPubMed

10.

Sacino AN, Brooks M, McKinney AB, Thomas MA, Shaw G, Golde TE, Giasson BI (2014) Brain Injection of α-Synuclein Induces Multiple Proteinopathies, Gliosis, and a Neuronal Injury Marker. J Neurosci 34:12368–12378, doi: 10.1523/JNEUROSCI. 2102-14.2014CrossRefPubMed

11.

Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ, Lee VM (2012) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953, doi: 10.1126/science.1227157CrossRefPubMedCentralPubMed

12.

Ulusoy A, Rusconi R, Perez-Revuelta BI, Musgrove RE, Helwig M, Winzen-Reichert B, Di Monte DA (2013) Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol Med 5:1051–1059. doi:10.1002/emmm.201302475CrossRefPubMedCentralPubMed

13.

Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ, Lee VM (2011) Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72(1):57–71, doi: 10.1016/j.neuron.2011.08.033CrossRefPubMedCentralPubMed

14.

Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ (2012) Exosomal cell-to-cell transmission of α synuclein oligomers. Mol Neurodegener 7:42, doi: 10.1186/1750-1326-7-42CrossRefPubMedCentralPubMed

15.

Schneider A, Simons M (2013) Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res 352:33–47, doi: 10.1007/s00441-012-1428-2CrossRefPubMedCentralPubMed

16.

Bae EJ, Yang NY, Song M, Lee CS, Lee JS, Jung BC, Lee HJ, Kim S, Masliah E, Sardi SP, Lee SJ (2014) Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein. Nat Commun 5:4755, doi: 10.1038/ncomms5755CrossRefPubMed

17.

Loeb JE, Cordier WS, Harris ME, Weitzman MD, Hope TJ (1999) Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element: implications for gene therapy. Hum Gene Ther 10:2295–2305, doi: 10.1089/10430349950016942CrossRefPubMed

18.

West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22:51–61CrossRefPubMed

19.

Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263CrossRefPubMed

20.

Gundersen HJ, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorensen FB, Vesterby A, West MJ (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96:857–881CrossRefPubMed

21.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682, doi: 10.1038/nmeth.2019CrossRefPubMed

22.

Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, London

23.

Mouton PR, Gokhale AM, Ward NL, West MJ (2002) Stereological length estimation using spherical probes. J Microsc 206:54–64CrossRefPubMed

24.

Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology–reconsidered. J Microsc 193:199–211CrossRefPubMed

25.

Kovacs GG, Wagner U, Dumont B, Pikkarainen M, Osman AA, Streichenberger N, Leisser I, Verchere J, Baron T, Alafuzoff I, Budka H, Perret-Liaudet A, Lachmann I (2012) An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology. Acta Neuropathol 124:37–50, doi: 10.1007/s00401-012-0964-xCrossRefPubMed

26.

Summerford C, Samulski RJ (1999) Viral receptors and vector purification: new approaches for generating clinical-grade reagents. Nat Med 5:587–588, doi: 10.1038/8470CrossRefPubMed

27.

Ulusoy A, Bjorklund T, Hermening S, Kirik D (2008) In vivo gene delivery for development of mammalian models for Parkinson's disease. Exp Neurol 209:89–100, doi: 10.1016/j.expneurol.2007.09.011CrossRefPubMed

28.

Lock M, Alvira M, Vandenberghe LH, Samanta A, Toelen J, Debyser Z, Wilson JM (2010) Rapid, simple, and versatile manufacturing of recombinant adeno-associated viral vectors at scale. Hum Gene Ther 21:1259–1271, doi: 10.1089/hum.2010.055CrossRefPubMedCentralPubMed

29.

Kalia M, Sullivan JM (1982) Brainstem projections of sensory and motor components of the vagus nerve in the rat. J Comp Neurol 211:248–265, doi: 10.1002/cne.902110304CrossRefPubMed

30.

Schwaber JS, Kapp BS, Higgins GA, Rapp PR (1982) Amygdaloid and basal forebrain direct connections with the nucleus of the solitary tract and the dorsal motor nucleus. J Neurosci 2:1424–1438PubMed

31.

ter Horst GJ, Luiten PG, Kuipers F (1984) Descending pathways from hypothalamus to dorsal motor vagus and ambiguus nuclei in the rat. J Auton Nerv Syst 11:59–75CrossRefPubMed

32.

van der Kooy D, Koda LY, McGinty JF, Gerfen CR, Bloom FE (1984) The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat. J Comp Neurol 224:1–24, doi: 10.1002/cne.902240102CrossRefPubMed

33.

Chiba T, Murata Y (1985) Afferent and efferent connections of the medial preoptic area in the rat: a WGA-HRP study. Brain Res Bull 14:261–272CrossRefPubMed

34.

Blessing WW, Li YW, Wesselingh SL (1991) Transneuronal transport of herpes simplex virus from the cervical vagus to brain neurons with axonal inputs to central vagal sensory nuclei in the rat. Neuroscience 42:261–274CrossRefPubMed

35.

Di Pasquale G, Chiorini JA (2006) AAV transcytosis through barrier epithelia and endothelium. Mol Ther 13:506–516, doi: 10.1016/j.ymthe.2005.11.007CrossRefPubMed

36.

Albanese A, Altavista MC, Rossi P (1986) Organization of central nervous system dopaminergic pathways. J Neural Transm Suppl 22:3–17PubMed

37.

Decressac M, Mattsson B, Lundblad M, Weikop P, Bjorklund A (2012) Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol Dis 45:939–953, doi: 10.1016/j.nbd.2011.12.013CrossRefPubMed

38.

Chu Y, Morfini GA, Langhamer LB, He Y, Brady ST, Kordower JH (2012) Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease. Brain 135:2058–2073, doi: 10.1093/brain/aws133CrossRefPubMed

39.

Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Bohm KJ, Winner B (2013) α-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288:21742–21754, doi: 10.1074/jbc.M113.451815CrossRefPubMedCentralPubMed

40.

Guo JL, Lee VM (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20:130–138, doi: 10.1038/nm.3457CrossRefPubMedCentralPubMed

Title: Neuron-to-neuron α-synuclein propagation in vivo is independent of neuronal injury
Authors: Ayse Ulusoy
Ruth E Musgrove
Raffaella Rusconi
Michael Klinkenberg
Michael Helwig
Anja Schneider
Donato A Di Monte
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-015-0198-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neuron-to-neuron α-synuclein propagation in vivo is independent of neuronal injury

Abstract

Introduction

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Results

Conclusions

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