[en] Understanding the progression of α-synuclein pathology in neurodegenerative diseases such as Parkinson's disease (PD) is a longstanding challenge. Here, a novel midbrain-hindbrain-assembloid model that recapitulates the spread of α-synuclein pathology observed in PD patients, akin to Braak's hypothesis, is presented. Initially, the presence α-synuclein pathology is demonstrated in the hindbrain organoids. Subsequently, sophisticated tissue engineering methods are employed to create midbrain-hindbrain assembloids. These assembloids allow investigation and description of the spreading of α-synuclein pathology, as it progresses from the hindbrain components to the midbrain regions within the integrated structure. It is observed that an increase in α-synuclein in the hindbrain can induce transfer of the pathology into the healthy midbrain, as well as cause changes at the synapse level. The presented model constitutes a robust in vitro platform for investigating the mechanisms underlying α-synuclein spreading and disease progression, and holding potential for the screening of prospective therapeutics targeting the pathological propagation in PD and related synucleinopathies.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
GOMEZ GIRO, Gemma ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
FRANGENBERG-HOFF, Daniela ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
VEGA GUTIERREZ, Daniela Maria ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
ZAGARE, Alise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
BARMPA, Kyriaki ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
ROBERTSON, Graham ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
Sabahi-Kaviani, Rahman; Department of Mechanical Engineering, Eindhoven University of Technology (TUE), Eindhoven, 5612 AE, The Netherlands
Haendler, Kristian; Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), 23538, Lübeck, Germany
Kruse, Nathalie; Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), 23538, Lübeck, Germany
Papastefanaki, Florentia; Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur Institute, Athens, 11521, Greece
Matsas, Rebecca; Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur Institute, Athens, 11521, Greece
Spielmann, Malte; Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein (UKSH), 23538, Lübeck, Germany
Luttge, Regina; Department of Mechanical Engineering, Eindhoven University of Technology (TUE), Eindhoven, 5612 AE, The Netherlands
SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
The LCSB Bioimaging Platform supported the microscopy work. The authors would also like to thank the private donors who support this work at the Luxembourg Centre for Systems Biomedicine. The authors would like to recognize the work of Dr. Nathasia Mudiwa Muwanigwa and Dr. Jennifer Modamio Chamarro on the characterization of iPSCs and the derivation of NESCs used in this manuscript. The research contained in this article was supported by the European Union's Horizon 2020 research and innovation programme H2020-FETPROACT-2018-01 under grant agreement 824070 (CONNECT). F.P. and R.M. want to acknowledge Hellenic Foundation for Research and Innovation Project 1019 DiseasePHENOTarget for their support. The use of existing iPSC lines obtained from previous studies was approved by the local ethical committee (Comit\u00E9 National d'Ethique de Recherche, CNER no 201901/01). Informed consent was obtained from all individuals donating samples to this study prior to the donation using a written form and protocol. Cell lines used in this study are summarized in Table S1 (Supporting Information).The LCSB Bioimaging Platform supported the microscopy work. The authors would also like to thank the private donors who support this work at the Luxembourg Centre for Systems Biomedicine. The authors would like to recognize the work of Dr. Nathasia Mudiwa Muwanigwa and Dr. Jennifer Modamio Chamarro on the characterization of iPSCs and the derivation of NESCs used in this manuscript. The research contained in this article was supported by the European Union's Horizon 2020 research and innovation programme H2020\u2010FETPROACT\u20102018\u201001 under grant agreement 824070 (CONNECT). F.P. and R.M. want to acknowledge Hellenic Foundation for Research and Innovation Project 1019 DiseasePHENOTarget for their support. The use of existing iPSC lines obtained from previous studies was approved by the local ethical committee (Comit\u00E9 National d'Ethique de Recherche, CNER no 201901/01). Informed consent was obtained from all individuals donating samples to this study prior to the donation using a written form and protocol. Cell lines used in this study are summarized in Table S1 (Supporting Information).
H. Braak, K. Del Tredici, U. Rüb, R. A. de Vos, E. N Jansen Steur, E. Braak, Neurobiol. Aging 2003, 24, 197.
K. Seidel, J. Mahlke, S. Siswanto, R. Krüger, H. Heinsen, G. Auburger, M. Bouzrou, L. T. Grinberg, H. Wicht, H. W. Korf, W. den Dunnen, U. Rüb, Brain Pathol. 2014, 25, 121.
M. G. Spillantini, M. L. Schmidt, V. M. Lee, J. Q. Trojanowski, R. Jakes, M. Goedert, Nature 1997, 388, 839.
M. H. Polymeropoulos, C. Lavedan, E. Leroy, S. E. Ide, A. Dehejia, A. Dutra, B. Pike, H. Root, J. Rubenstein, R. Boyer, E. S. Stenroos, S. Chandrasekharappa, A. Athanassiadou, T. Papapetropoulos, W. G. Johnson, A. M. Lazzarini, R. C. Duvoisin, G. Di Iorio, L. I. Golbe, R. L. Nussbaum, Science 1997, 276, 2045.
R. Krüger, W. Kuhn, T. Müller, D. Woitalla, M. Graeber, S. Kösel, H. Przuntek, J. T. Epplen, L. Schöls, O. Riess, Nat. Genet. 1998, 18, 106.
J. J. Zarranz, J. Alegre, J. C. Gómez-Esteban, E. Lezcano, R. Ros, I. Ampuero, L. Vidal, J. Hoenicka, O. Rodriguez, B. Atarés, V. Llorens, E. G. Tortosa, T. del Ser, D. G. Muñoz, J. G. de Yebenes, Ann. Neurol. 2004, 55, 164.
S. Appel-Cresswell, C. Vilarino-Guell, M. Encarnacion, H. Sherman, I. Yu, B. Shah, D. Weir, C. Thompson, C. Szu-Tu, J. Trinh, J. O. Aasly, A. Rajput, A. H. Rajput, A. Jon Stoessl, M. J. Farrer, Mov. Disord. 2013, 28, 811.
D. Hoffman-Zacharska, D. Koziorowski, O. A. Ross, M. Milewski, J. Poznanski, M. Jurek, Z. K. Wszolek, A. Soto-Ortolaza, J. Slawek, P. Janik, Z. Jamrozik, A. Potulska-Chromik, B. Jasinska-Myga, G. Opala, A. Krygowska-Wajs, K. Czyzewski, D. W. Dickson, J. Bal, A. Friedman, Parkinsonism Relat. Disord. 2013, 19, 1057.
A. P. Kiely, Y. T. Asi, E. Kara, P. Limousin, H. Ling, P. Lewis, C. Proukakis, N. Quinn, A. J. Lees, J. Hardy, T. Revesz, H. Houlden, J. L. Holton, Acta Neuropathol. 2013, 125, 753.
P. Pasanen, L. Myllykangas, M. Siitonen, A. Raunio, S. Kaakkola, J. Lyytinen, P. J. Tienari, M. Pöyhönen, A. Paetau, Neurobiol. Aging 2014, 35, 2180.
A. B. Singleton, M. Farrer, J. Johnson, A. Singleton, S. Hague, J. Kachergus, M. Hulihan, T. Peuralinna, A. Dutra, R. Nussbaum, S. Lincoln, A. Crawley, M. Hanson, D. Maraganore, C. Adler, M. R. Cookson, M. Muenter, M. Baptista, D. Miller, J. Blancato, J. Hardy, K. Gwinn-Hardy, Science 2003, 302, 841.
L. Fonseca-Ornelas, J. M. S. Stricker, S. Soriano-Cruz, B. Weykopf, U. Dettmer, C. R. Muratore, C. R. Scherzer, D. J. Selkoe, npj Parkinson's Dis. 2022, 8, 118.
S. Zhang, R. Zhu, B. Pan, H. Xu, M. F. Olufemi, R. J. Gathagan, Y. Li, L. Zhang, J. Zhang, W. Xiang, E. M. Kagan, X. Cao, C. Yuan, S. J. Kim, C. K. Williams, S. Magaki, H. V. Vinters, H. A. Lashuel, B. A. Garcia, E. James Petersson, J. Q. Trojanowski, V. M. Lee, C. Peng, Nat. Neurosci. 2023, 26, 213.
D. W. Miller, S. M. Hague, J. Clarimon, M. Baptista, K. Gwinn-Hardy, M. R. Cookson, A. B. Singleton, Neurology 2004, 62, 1835.
I. Wurster, C. Quadalti, M. Rossi, A. K. Hauser, C. Deuschle, C. Schulte, K. Waniek, I. Lachmann, C. la Fougere, K. Doppler, T. Gasser, B. Bender, P. Parchi, K. Brockmann, npj Parkinson's Dis. 2022, 8, 117.
E. Vasili, A. Dominguez-Meijide, M. Flores-León, M. Al-Azzani, A. Kanellidi, R. Melki, L. Stefanis, T. F. Outeiro, Mol. Neurobiol. 2022, 59, 1273.
J. C. Sang, E. Hidari, G. Meisl, R. T. Ranasinghe, M. G. Spillantini, D. Klenerman, Commun. Biol. 2021, 4, 613.
R. Pinto-Costa, E. Harbachova, P. La Vitola, D. A. Di Monte, Neurotherapeutics 2022, 20, 83.
E. Angot, J. A. Steiner, C. M. Lema Tomé, P. Ekström, B. Mattsson, A. Björklund, P. Brundin, PLoS One 2012, 7, e39465.
W. Peelaerts, L. Bousset, A. Van der Perren, A. Moskalyuk, R. Pulizzi, M. Giugliano, C. Van den Haute, R. Melki, V. Baekelandt, Nature 2015, 522, 340.
S. Zhang, E. Eitan, T. Y. Wu, M. P. Mattson, Neurobiol. Aging 2017, 61, 52.
H. Scheiblich, C. Dansokho, D. Mercan, S. V. Schmidt, L. Bousset, L. Wischhof, F. Eikens, A. Odainic, J. Spitzer, A. Griep, S. Schwartz, D. Bano, E. Latz, R. Melki, M. T. Heneka, Cell 2021, 184, 5089.
M. X. Henderson, E. J. Cornblath, A. Darwich, B. Zhang, H. Brown, R. J. Gathagan, R. M. Sandler, D. S. Bassett, J. Q. Trojanowski, V. M. Y. Lee, Nat. Neurosci. 2019, 22, 1248.
S. Kim, S. H. Kwon, T. I. Kam, N. Panicker, S. S. Karuppagounder, S. Lee, J. H. Lee, W. R. Kim, M. Kook, C. A. Foss, C. Shen, H. Lee, S. Kulkarni, P. J. Pasricha, G. Lee, M. G. Pomper, V. L. Dawson, T. M. Dawson, H. S. Ko, Neuron 2019, 103, 627.
J. Y. Vargas, C. Grudina, C. Zurzolo, Ageing Res. Rev. 2019, 50, 89.
J. P. Anderson, D. E. Walker, J. M. Goldstein, R. de Laat, K. Banducci, R. J. Caccavello, R. Barbour, J. Huang, K. Kling, M. Lee, L. Diep, P. S. Keim, X. Shen, T. Chataway, M. G. Schlossmacher, P. Seubert, D. Schenk, S. Sinha, W. P. Gai, T. J. Chilcote, J. Biol. Chem. 2006, 281, 29739.
N. V. Mohamed, J. Sirois, J. Ramamurthy, M. Mathur, P. Lépine, E. Deneault, G. Maussion, M. Nicouleau, C. X. Chen, N. Abdian, V. Soubannier, E. Cai, H. Nami, R. A. Thomas, D. Wen, M. Tabatabaei, L. K. Beitel, K. Singh Dolt, J. Karamchandani, J. A. Stratton, T. Kunath, E. A. Fon, T. M. Durcan, Brain Commun. 2021, 3, fcab223.
M. N. Muwanigwa, J. Modamio-Chamarro, P. M. A. Antony, G. Gomez-Giro, R. Krüger, S. Bolognin, J. C. Schwamborn, Mol. Cell. Neurosci. 2024, 128, 103919.
L. R. Hernandez-Miranda, T. Müller, C. Birchmeier, Dev. Biol. 2016, 432, 34.
K. Muguruma, A. Nishiyama, H. Kawakami, K. Hashimoto, Y. Sasai, Cell Rep. 2015, 10, 537.
N. Eura, T. K. Matsui, J. Luginbühl, M. Matsubayashi, H. Nanaura, T. Shiota, K. Kinugawa, N. Iguchi, T. Kiriyama, C. Zheng, T. Kouno, Y. J. Lan, P. Kongpracha, P. Wiriyasermkul, Y. M. Sakaguchi, R. Nagata, T. Komeda, N. Morikawa, F. Kitayoshi, M. Jong, S. Kobashigawa, M. Nakanishi, M. Hasegawa, Y. Saito, T. Shiromizu, Y. Nishimura, T. Kasai, M. Takeda, H. Kobayashi, Y. Inagaki, et al., Front. Neurosci. 2020, 14, 538.
P. Valiulahi, V. Vidyawan, L. Puspita, Y. Oh, V. B. Juwono, P. Sittipo, G. Friedlander, D. Yahalomi, J. W. Sohn, Y. K. Lee, J. K. Yoon, J. W. Shim, Stem Cell Rep. 2021, 16, 1938.
A. Zagare, M. Gobin, A. S. Monzel, J. C. Schwamborn, STAR Protoc. 2021, 2, 100524.
A. S. Monzel, L. M. Smits, K. Hemmer, S. Hachi, E. L. Moreno, T. van Wuellen, J. Jarazo, J. Walter, I. Brüggemann, I. Boussaad, E. Berger, R. M. T. Fleming, S. Bolognin, J. C. Schwamborn, Stem Cell Rep. 2017, 8, 1144.
J. Andersen, O. Revah, Y. Miura, N. Thom, N. D. Amin, K. W. Kelley, M. Singh, X. Chen, M. V. Thete, E. M. Walczak, H. Vogel, H. C. Fan, S. P. Paşca, Cell 2020, 183, 1913.
R. H. Kutner, X. Y. Zhang, J. Reiser, Nat. Protoc. 2009, 4, 495.
K. Miyamichi, F. Amat, F. Moussavi, C. Wang, I. Wickersham, N. R. Wall, H. Taniguchi, B. Tasic, Z. J. Huang, Z. He, E. M. Callaway, M. A. Horowitz, L. Luo, Nature 2011, 472, 191.
F. Osakada, E. M. Callaway, Nat. Protoc. 2013, 8, 1583.
T. Stuart, A. Butler, P. Hoffman, C. Hafemeister, E. Papalexi, W. M. Mauck3rd, Y. Hao, M. Stoeckius, P. Smibert, R. Satija, Cell 2019, 177, 1888.
E. Becht, L. McInnes, J. Healy, C. A. Dutertre, I. W. H. Kwok, L. G. Ng, F. Ginhoux, E. W. Newell, Nat. Biotechnol. 2018, 37, 38.
S. Ben-Ari Fuchs, I. Lieder, G. Stelzer, Y. Mazor, E. Buzhor, S. Kaplan, Y. Bogoch, I. Plaschkes, A. Shitrit, N. Rappaport, A. Kohn, R. Edgar, L. Shenhav, M. Safran, D. Lancet, Y. Guan-Golan, D. Warshawsky, R. Shtrichman, OMICS 2016, 20, 139.
O. Franzén, L. M. Gan, J. L. M. Björkegren, Database 2019, 2019, baz046.
I. Stojkovska, W. Y. Wani, F. Zunke, N. R. Belur, E. A. Pavlenko, N. Mwenda, K. Sharma, L. Francelle, J. R. Mazzulli, Neuron 2021, 110, 436.
S. Bolognin, M. Fossépré, X. Qing, J. Jarazo, J. Scancar, E. L. Moreno, S. L. Nickels, K. Wasner, N. Ouzren, J. Walter, A. Grünewald, E. Glaab, L. Salamanca, R. M. T. Fleming, P. M. A. Antony, J. C. Schwamborn, Adv. Sci. 2019, 6, 1800927.
R. Habibey, S. Latifi, H. Mousavi, M. Pesce, E. Arab-Tehrany, A. Blau, Sci. Rep. 2017, 7, 8558.
P. Rifes, M. Isaksson, G. S. Rathore, P. Aldrin-Kirk, O. K. Møller, G. Barzaghi, J. Lee, K. L. Egerod, D. M. Rausch, M. Parmar, T. H. Pers, T. Laurell, A. Kirkeby, Nat. Biotechnol. 2020, 38, 1265.
K. Imaizumi, T. Sone, K. Ibata, K. Fujimori, M. Yuzaki, W. Akamatsu, H. Okano, Stem Cell Rep. 2015, 5, 1010.
S. M. Chambers, C. A. Fasano, E. P. Papapetrou, M. Tomishima, M. Sadelain, L. Studer, Nat. Biotechnol. 2009, 27, 275.
C. Kiecker, A. Lumsden, Annu. Rev. Neurosci. 2012, 35, 347.
E. S. Lippmann, C. E. Williams, D. A. Ruhl, M. C. Estevez-Silva, E. R. Chapman, J. J. Coon, R. S. Ashton, Stem Cell Rep. 2015, 4, 632.
S. T. Waters, M. Lewandoski, Development 2006, 133, 1991.
R. L. Stornetta, C. J. Macon, T. M. Nguyen, M. B. Coates, P. G. Guyenet, Brain Struct. Funct. 2012, 218, 455.
B. A. Bari, V. Chokshi, K. Schmidt, Neural Regener. Res. 2020, 15, 1006.
K. Taylor, E. Lester, B. Hudson, S. Ritter, Physiol. Behav. 2007, 90, 744.
L. Tricoire, T. Vitalis, Front. Neural Circuits 2012, 6, 82.
D. D. Kline, K. N. Takacs, E. Ficker, D. L. Kunze, J. Neurophysiol. 2002, 88, 2736.
R. L. Haining, A.-M. C. Neuromelanin, Neural Regener. Res. 2017, 12, 372.
A. Fiorenzano, E. Sozzi, M. Birtele, J. Kajtez, J. Giacomoni, F. Nilsson, A. Bruzelius, Y. Sharma, Y. Zhang, B. Mattsson, J. Emnéus, D. R. Ottosson, P. Storm, M. Parmar, Nat. Commun. 2021, 12, 7302.
B. A. Hijaz, L. A. Volpicelli-Daley, Mol. Neurodegener. 2020, 15, 19.
S. Grealish, A. Heuer, T. Cardoso, A. Kirkeby, M. Jönsson, J. Johansson, A. Björklund, J. Jakobsson, M. Parmar, Stem Cell Rep. 2015, 4, 975.
G. Ugolini, J. Comp. Neurol. 1995, 356, 457.
R. Etessami, K. K. Conzelmann, B. Fadai-Ghotbi, B. Natelson, H. Tsiang, P. E. Ceccaldi, J. Gen. Virol. 2000, 81, 2147.
T. T. Kanagasabapathi, D. Ciliberti, S. Martinoia, W. J. Wadman, M. M. Decré, Front. Neuroeng. 2011, 4, 13.
C. Román-Vendrell, A. T. Medeiros, J. B. Sanderson, H. Jiang, T. Bartels, J. R. Morgan, Front. Neurosci. 2021, 15, 639414.
T. C. Südhof, Nature 2008, 455, 903.
L. M. Smits, S. Magni, K. Kinugawa, K. Grzyb, J. Luginbühl, S. Sabate-Soler, S. Bolognin, J. W. Shin, E. Mori, A. Skupin, J. C. Schwamborn, Cell Tissue Res. 2020, 382, 463.
I. Stojkovska, J. R. Mazzulli, STAR Protoc. 2021, 2, 100372.
J. Jo, L. Yang, H. D. Tran, W. Yu, A. X. Sun, Y. Y. Chang, B. C. Jung, S. J. Lee, T. Y. Saw, B. Xiao, A. T. T. Khoo, L. P. Yaw, J. J. Xie, H. Lokman, W. Y. Ong, G. G. Y. Lim, K. L. Lim, E. K. Tan, H. H. Ng, H. S. Je, Ann. Neurol. 2021, 90, 490.
H. Fukusumi, K. Togo, M. Sumida, M. Nakamori, S. Obika, K. Baba, T. Shofuda, D. Ito, H. Okano, H. Mochizuki, Y. Kanemura, FEBS Open Bio 2021, 11, 354.
R. Rusconi, A. Ulusoy, H. Aboutalebi, D. A. Di Monte, Aging Cell 2018, 17, e12727.
I. C. Brás, T. F. Outeiro, Cells 2021, 10, 375.
N. Ramalingam, S. X. Jin, T. E. Moors, L. Fonseca-Ornelas, K. Shimanaka, S. Lei, H. P. Cam, A. H. Watson, L. Brontesi, L. Ding, D. Y. Hacibaloglu, H. Jiang, S. J. Choi, E. Kanter, L. Liu, T. Bartels, S. Nuber, D. Sulzer, E. V. Mosharov, W. V. Chen, S. Li, D. J. Selkoe, U. Dettmer, npj Parkinson's Dis. 2023, 9, 4.
D. L. Fortin, V. M. Nemani, S. M. Voglmaier, M. D. Anthony, T. A. Ryan, R. H. Edwards, J. Neurosci. 2005, 25, 10913.
M. G. Choi, M. J. Kim, D. G. Kim, R. Yu, Y. N. Jang, W. J. Oh, PLoS One 2018, 13, e0195339.
K. A. Malkus, E. Tsika, H. Ischiropoulos, Mol. Neurodegener. 2009, 4, 24.
P. Borghammer, M. K. Just, J. Horsager, C. Skjærbæk, A. Raunio, E. H. Kok, S. Savola, S. Murayama, Y. Saito, L. Myllykangas, N. Van Den Berge, npj Parkinson's Dis. 2022, 8, 166.
P. Borghammer, J. Horsager, K. Andersen, N. Van Den Berge, A. Raunio, S. Murayama, L. Parkkinen, L. Myllykangas, Neurobiol. Dis. 2021, 161, 105557.
Y. Zhu, X. Zhang, L. Sun, Y. Wang, Y. Zhao, Adv. Mater. 2023, 35, 2210083.
A. Bastiaens, R. Sabahi-Kaviani, R. Luttge, Front. Neurosci. 2020, 14, 666.
