ZFIN ID: ZDB-LAB-030923-2
Schmid Lab
PI/Director: Schmid, Bettina
Contact Person: Schmid, Bettina
Email: bettina.schmid@dzne.de
URL: http://www.biochemie.abi.med.uni-muenchen.de/research/haass/zebrafish/index.html
Address: German Center for Neurodegenerative Diseases (DZNE) - Munich site Feodor-Lynen-Str. 17 Munich 81377 Germany
Country: Germany
Phone: 49-89-4400 46 511
Line Designation: mde

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Our group uses the advantages of the zebrafish, Danio rerio, as an in vivo model system to address some of unresolved questions in Alzheimer’s disease, Parkinson’s disease, Frontotemporal Lobar Degeneration (FTLD), and Amyotrophic lateral Sclerosis (ALS). Our research has four major aims:

1. Generation of transgenic zebrafish
Animal models are crucial in understanding disease mechanisms and to design therapeutic strategies. We generated a powerful Gal4-UAS based trangenesis vector system that allowed us to generate numerous transgenic zebrafish lines. Transgenic expression of human disease associated genes enables us to recapitulate hallmarks of the respective human disease in zebrafish.

2. Generation of knock-downs and mutants
Genes associated with neurodegenerative diseases are being investigated for their in vivo function in zebrafish. Interestingly, very little is known about the physiological function of genes such as TDP-43 - despite their well-established role in ALS and FTD. Manipulation of protein levels mediated by injection of antisense gripNAs and subsequent analysis of the generated phenotypes enable us to gain insight into their physiological function. Additionally mutations in disease relevant genes are currently established by zinc finger nuclease mediated genome editing.

3. In vivo imaging
One of the great advantages of the zebrafish is the optical transparency during early larval stages. This allows expression of fluorescent reporters and in vivo imaging at sub-cellular resolution. For example, we were able to in vivo image neuronal cell death in Tg(HuC:TauP301L) larvae.

4. Drug evaluation in disease models
The transgenic disease models generated are great tools to search for disease modifying drugs. Zebrafish larvae are small in size (< 1mm) and live in an aqueous environment where chemicals can be easily applied. Zebrafish therefore represent a wonderful tool to assay for disease modifying drugs in vivo.

van Bebber, Frauke Post-Doc Hasenkamp, Laura Graduate Student Strecker, Katrin Graduate Student
Rojas, Roberto Rojas Fish Facility Staff Hruscha, Alexander Technical Staff

Cunha, M.I., Su, M., Cantuti-Castelvetri, L., Müller, S.A., Schifferer, M., Djannatian, M., Alexopoulos, I., van der Meer, F., Winkler, A., van Ham, T.J., Schmid, B., Lichtenthaler, S.F., Stadelmann, C., Simons, M. (2020) Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis. The Journal of experimental medicine. 217(5):
Zambusi, A., Pelin Burhan, Ö., Di Giaimo, R., Schmid, B., Ninkovic, J. (2020) Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon. Cells. 9(2):
Djannatian, M., Timmler, S., Arends, M., Luckner, M., Weil, M.T., Alexopoulos, I., Snaidero, N., Schmid, B., Misgeld, T., Möbius, W., Schifferer, M., Peles, E., Simons, M. (2019) Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS. Nature communications. 10:4794
Ohki, Y., Wenninger-Weinzierl, A., Hruscha, A., Asakawa, K., Kawakami, K., Haass, C., Edbauer, D., Schmid, B. (2017) Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration. Molecular neurodegeneration. 12:6
Eichner, R., Heider, M., Fernández-Sáiz, V., van Bebber, F., Garz, A.K., Lemeer, S., Rudelius, M., Targosz, B.S., Jacobs, L., Knorn, A.M., Slawska, J., Platzbecker, U., Germing, U., Langer, C., Knop, S., Einsele, H., Peschel, C., Haass, C., Keller, U., Schmid, B., Götze, K.S., Kuster, B., Bassermann, F. (2016) Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nature medicine. 22(7):735-43
Hasenkamp, L. (2016) ALS and FTLD associated FUS in zebrafish investigating disease mechanisms in vivo : investigating disease mechanisms in vivo. Thesis.
Janssens, J., Philtjens, S., Kleinberger, G., Van Mossevelde, S., van der Zee, J., Cacace, R., Engelborghs, S., Sieben, A., Banzhaf-Strathmann, J., Dillen, L., Merlin, C., Cuijt, I., Robberecht, C., Schmid, B., Santens, P., Ivanoiu, A., Vandenbulcke, M., Vandenberghe, R., Cras, P., De Deyn, P.P., Martin, J.J., Maudsley, S., Haass, C., Cruts, M., Van Broeckhoven, C., Belgian Neurology (BELNEU) consortium (2015) Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains. Acta neuropathologica communications. 3:68
Solchenberger, B., Russell, C., Kremmer, E., Haass, C., Schmid, B. (2015) Granulin Knock Out Zebrafish Lack Frontotemporal Lobar Degeneration and Neuronal Ceroid Lipofuscinosis Pathology. PLoS One. 10:e0118956
Hruscha, A., Schmid, B. (2015) Generation of Zebrafish Models by CRISPR /Cas9 Genome Editing. Methods in molecular biology (Clifton, N.J.). 1254:341-50
Hruscha, A., Krawitz, P., Rechenberg, A., Heinrich, V., Hecht, J., Haass, C., and Schmid, B. (2013) Efficient CRISPR/Cas9 genome editing with low off-target effects in zebrafish. Development (Cambridge, England). 140(24):4982-4987
Schmid, B., and Haass, C. (2013) Genomic editing opens new avenues for zebrafish as a model for neurodegeneration. Journal of neurochemistry. 127(4):461-470
van Bebber, F., Hruscha, A., Willem, M., Schmid, B., and Haass, C. (2013) Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. Journal of neurochemistry. 127(4):471-481
Fleck, D., van Bebber, F., Colombo, A., Galante, C., Schwenk, B.M., Rabe, L., Hampel, H., Novak, B., Kremmer, E., Tahirovic, S., Edbauer, D., Lichtenthaler, S.F., Schmid, B., Willem, M., and Haass, C. (2013) Dual Cleavage of Neuregulin 1 Type III by BACE1 and ADAM17 Liberates Its EGF-Like Domain and Allows Paracrine Signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(18):7856-7869
Hogl, S., van Bebber, F., Dislich, B., Kuhn, P.H., Haass, C., Schmid, B., and Lichtenthaler, S.F. (2013) Label-free quantitative analysis of the membrane proteome of Bace1 protease knock-out zebrafish brains. Proteomics. 13(9):1519-27
Grisham, R.C., Kindt, K., Finger-Baier, K., Schmid, B., and Nicolson, T. (2013) Mutations in ap1b1 Cause Mistargeting of the Na(+)/K(+)-ATPase Pump in Sensory Hair Cells. PLoS One. 8(4):e60866
Schmid, B., Hruscha, A., Hogl, S., Banzhaf-Strathmann, J., Strecker, K., van der Zee, J., Teucke, M., Eimer, S., Hegermann, J., Kittelmann, M., Kremmer, E., Cruts, M., Solchenberger, B., Hasenkamp, L., van Bebber, F., Van Broeckhoven, C., Edbauer, D., Lichtenthaler, S.F., and Haass, C. (2013) Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proceedings of the National Academy of Sciences of the United States of America. 110(13):4986-91
Gut, P., Baeza-Raja, B., Andersson, O., Hasenkamp, L., Hsiao, J., Hesselson, D., Akassoglou, K., Verdin, E., Hirschey, M.D., and Stainier, D.Y. (2013) Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nature Chemical Biology. 9(2):97-104
Plucinska, G., Paquet, D., Hruscha, A., Godinho, L., Haass, C., Schmid, B., and Misgeld, T. (2012) In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system. The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(46):16203-16212
van Bebber, F., Paquet, D., Hruscha, A., Schmid, B., and Haass, C. (2010) Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish. Neurobiology of disease. 39(3):265-271
Dormann, D., Rodde, R., Edbauer, D., Bentmann, E., Fischer, I., Hruscha, A., Than, M.E., Mackenzie, I.R., Capell, A., Schmid, B., Neumann, M., and Haass, C. (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. The EMBO journal. 29(16):2841-2857
Fett, M.E., Pilsl, A., Paquet, D., van Bebber, F., Haass, C., Tatzelt, J., Schmid, B., and Winklhofer, K.F. (2010) Parkin Is Protective against Proteotoxic Stress in a Transgenic Zebrafish Model. PLoS One. 5(7):e11783
Paquet, D., Schmid, B., and Haass, C. (2010) Transgenic Zebrafish as a Novel Animal Model to Study Tauopathies and Other Neurodegenerative Disorders in vivo. Neuro-degenerative Diseases. 7(1-3):99-102
Paquet, D., Bhat, R., Sydow, A., Mandelkow, E.M., Berg, S., Hellberg, S., Fälting, J., Distel, M., Köster, R.W., Schmid, B., and Haass, C. (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J. Clin. Invest.. 119(5):1382-1395
Rojas-Muñoz, A., Rajadhyksha, S., Gilmour, D., van Bebber, F., Antos, C., Rodríguez Esteban, C., Nüsslein-Volhard, C., and Izpisúa Belmonte, J.C. (2009) ErbB2 and ErbB3 regulate amputation-induced proliferation and migration during vertebrate regeneration. Developmental Biology. 327(1):177-190
Dooley, K.A., Fraenkel, P.G., Langer, N.B., Schmid, B., Davidson, A.J., Weber, G., Chiang, K., Foott, H., Dwyer, C., Wingert, R.A., Zhou, Y., Paw, B.H., Zon, L.I., and Tübingen 2000 Screen Consortium . (2008) montalcino, A zebrafish model for variegate porphyria. Experimental hematology. 36(9):1132-1142
Shankaran, S.S., Capell, A., Hruscha, A.T., Fellerer, K., Neumann, M., Schmid, B., and Haass, C. (2008) FTLD-U linked missense mutations in the progranulin gene reduce progranulin production and secretion. The Journal of biological chemistry. 283(3):1744-1753
Schiffer, N.W., Broadley, S.A., Hirschberger, T., Tavan, P., Kretzschmar, H.A.,Giese, A., Haass, C., Hartl, U.F., and Schmid, B. (2007) Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model. The Journal of biological chemistry. 282(12):9195-9203
Geisler, R., Rauch, G.J., Geiger-Rudolph, S., Albrecht, A., van Bebber, F., Berger, A., Busch-Nentwich, E., Dahm, R., Dekens, M.P., Dooley, C., Elli, A.F.,Gehring, I., Geiger, H., Geisler, M., Glaser, S., Holley, S., Huber, M., Kerr, A., Kirn, A., Knirsch, M., Konantz, M., Kuchler, A.M., Maderspacher, F., Neuhauss, S.C., Nicolson, T., Ober, E.A., Praeg, E., Ray, R., Rentzsch, B., Rick, J.M., Rief, E., Schauerte, H.E., Schepp, C.P., Schonberger, U., Schonthaler, H.B., Seiler, C., Sidi, S., Söllner, C., Wehner, A., Weiler, C., Nüsslein-Volhard, C. (2007) Large-scale mapping of mutations affecting zebrafish development. BMC Genomics. 8(1):11
Krawitz, P., Haffner, C., Fluhrer, R., Steiner, H., Schmid, B., and Haass, C. (2005) Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenlin in homologues SPPL2b and SPPL3. The Journal of biological chemistry. 280(47):39515-39523
Wingert, R.A., Galloway, J.L., Barut, B., Foott, H., Fraenkel, P., Axe, J.L., Weber, G.J., Dooley, K., Davidson, A.J., Schmid, B., Paw, B.H., Shaw, G.C., Kingsley, P., Palis, J., Schubert, H., Chen, O., Kaplan, J., Zon, L.I., Tübingen 2000 Screen Consortium. (2005) Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature. 436(7053):1035-1039
Kramer, C., Mayr, T., Nowak, M., Schumacher, J., Runke, G., Bauer, H., Wagner, D., Schmid, B., Imai, Y., Talbot, W., Mullins, M., and Hammerschmidt, M. (2002) Maternally supplied smad5 is required for ventral specification in zebrafish embryos prior to zygotic bmp signaling. Developmental Biology. 250(2):263-279
Willot, V., Mathieu, J., Lu, Y., Schmid, B., Sidi, S., Yan, Y.-L., Postlethwait, J.H., Mullins, M., Rosa, F., and Peyriéras, N. (2002) Cooperative action of ADMP- and BMP-mediated pathways in regulating cell fates in the zebrafish gastrula. Developmental Biology. 241(1):59-78
Kelsh, R.N., Schmid, B., and Eisen, J.S. (2000) Genetic analysis of melanophore development in zebrafish embryos. Developmental Biology. 225(2):277-293
Schmid, B., Fürthauer, M., Connors, S.A., Trout, J., Thisse, B., Thisse, C., and Mullins, M.C. (2000) Equivalent genetic roles for bmp7/snailhouse and bmp2b/swirl in dorsoventral pattern formation. Development (Cambridge, England). 127(5):957-967
Schmid, B. (2000) Molecular characterization of the dorsalized zebrafish mutants swirl, somitabun and snailhouse. Ph.D. Thesis. :77p
Geisler, R., Rauch, G.J., Baier, H., van Bebber, F., Brobeta, L., Dekens, M.P., Finger, K., Fricke, C., Gates, M.A., Geiger, H., Geiger-Rudolph, S., Gilmour, D., Glaser, S., Gnugge, L., Habeck, H., Hingst, K., Holley, S., Keenan, J., Kirn, A., Knaut, H., Lashkari, D., Maderspacher, F., Martyn, U., Neuhauss, S., Neumann, C., Nicolson, T., Pelegri, F., Ray, R., Rick, J.M., Roehl, H., Roeser, T., Schauerte, H.E., Schier, A.F., Schönberger, U., Schönthaler, H.-B., Schulte-Merker, S., Seydler, C., Talbot, W.S., Weiler, C., Nüsslein-Volhard, C., and Haffter, P. (1999) A radiation hybrid map of the zebrafish genome. Nature Genetics. 23(1):86-89
Campione, M., Steinbeisser, H., Schweickert, A., Deissler, K., van Bebber, F., Lowe, L.A., Nowotschin, S., Viebahn, C., Haffter, P., Kuehn, M.R., and Blum, M. (1999) The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development (Cambridge, England). 126(6):1225-1234
Nguyen, V.H., Schmid, B., Trout, J., Connors, S.A., Ekker, M., and Mullins, M.C. (1998) Ventral and lateral regions of the zebrafish gastrula, including the neural crest progenitors, are established by bmp2b/swirl pathway of genes. Developmental Biology. 199:93-110