Molecular Neurobiology
Research Summary:
The Storkebaum lab combines Drosophila and mouse genetics to decipher the molecular mechanisms underlying motor neurodegenerative disorders. Our primary focus is on Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by heterozygous mutations in cytoplasmic tRNA synthetases, and on amyotrophic lateral sclerosis (ALS) caused by heterozygous mutations in the DNA/RNA-binding protein FUS. In addition, we are performing a forward genetic screen in Drosophila to identify genes required for axonal maintenance.
We use the fruit fly, Drosophila melanogaster, as an exploratory genetic model for these diseases, as it is ideally suited to conduct genetic screens, which allow for the identification of putative disease-modifying genes. Identified modifiers are subsequently validated, not only in Drosophila, but also in mouse models, as these are the most disease-relevant preclinical models currently available. This approach should allow us to gain novel insights into the molecular pathogenesis, and may result in the identification of therapeutic targets for these incurable neurodegenerative disorders.
| Contact | |
| Name: | Erik Storkebaum |
| Telephone: | +31 (0) 625 76 60 73 |
| Email: | erik.storkebaum@donders.ru.nl |
| Visiting address: | Donders Centre for Neuroscience Heyendaelseweg 135 6525 AJ Nijmegen The Netherlands |
| Postal address: | Department of Molecular Neurobiology Donders Centre for Neuroscience P.O. Box 9010 Internal mailbox 91 6500 GL Nijmegen The Netherlands |
| Key grants and prizes |
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Research grants 2022 - NWO-ENW-M grant (360,000€) 2017 – Partner in JPND network grant “Common architecture of local proteome, transcriptome and translatome across motor neuron disorders”. 224,000€ for our lab 2017 - Muscular Dystrophy Association (MDA) grant “Unraveling mechanisms by which mutant tRNA synthetases cause CMT neuropathy”. 291,000$ Prizes and awards 2005 - Galenus prize (Belgium), together with Diether Lambrechts, for preclinical pharmacological studies on the therapeutic potential of VEGF for ALS. 2005 - Baron Simonart prize, awarded for my PhD thesis: "Role and therapeutic potential of VEGF in motor neuron degeneration: a study in transgenic mice and rats." 2001 - Pharmaleuven prize (best undergraduate thesis), University of Leuven, Belgium. |
| Key publications |
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Storkebaum E, Rosenblum K, Sonenberg N. Messenger RNA translation defects in neurodegenerative diseases. New Engl J Med, 2023; 388: 1015-30. DOI: 10.1056/NEJMra2215795. Zuko A, Mallik M, Thompson R, Spaulding E, Wienand A, Been M, Tadenev A, van Bakel N, Sijlmans C, Santos L, Bussmann J, Catinozzi M, Das S, Kulshrestha D, Burgess R, Ignatova Z, Storkebaum E. tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase. Science, 2021; 373: 1161-1166. (https://www.science.org/stoken/author-tokens/ST-13/full) Spaulding E, Hines T, Bais P, Tadenev A, Schneider R, Jewett D, Pattavina B, Pratt S, Morelli K, Stum M, Hill D, Gobet C, Pipis M, Reilly M, Jennings M, Horvath R, Bai Y, Shy M, Alvarez-Castelao, Schuman E, Bogdanik L, Storkebaum E, Burgess R. The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science, 2021; 373: 1156-1161. Mallik M, Catinozzi M, Clemens H, Zhang L, Wagner M, Bussmann J, Bittern J, Mersmann S, Klämbt C, Drexler H, Huynen M, Vaquerizas J, Storkebaum E. Xrp1 genetically interacts with the ALS-associated FUS ortholog caz and mediates its toxicity. Journal of Cell Biology 2018; jcb.201802151. doi: 10.1083/jcb.201802151. Scekic-Zahirovic J, Sendscheid O, El Oussini H, Jambeau M, Ying S, Mersmann S, Wagner M, Dieterlé S, Sinniger J, Dirrig-Grosch S, Drenner K, Birling M, Qui J, Zhou Y, Li H, Fu X, Rouaux C, Shelkovnikova T, Witting A, Ludolph A, Kiefer F, Storkebaum E*, Lagier-Tourenne C*, Dupuis L*. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO Journal 2016; 35(10): 1077-97. *corresponding authors. Niehues S, Bussmann J, Steffes G, Erdmann I, Köhrer C, Sun L, Wagner M, Schäfer K, Wang G, Koerdt SN, Stum M, RajBhandary UL, Thomas U, Aberle H, Burgess RW, Yang X-L, Dieterich D, Storkebaum E. Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nature Communications 2015; 6:7520 doi: 10.1038/ncomms8520. Erdmann I, Marter K, Kobler O, Niehues S, Abele J, Müller A, Bussmann J, Storkebaum E, Ziv T, Thomas U, Dieterich D. Cell-selective labeling of proteomes in Drosophila melanogaster. Nature Communications 2015; 6:7521 doi: 10.1038/ncomms8521. Storkebaum E, Ruiz de Almodovar C, Meens M, Zacchigna S, Mazzone M, Vanhoutte G, Vinckier S, Miskiewicz K, Poesen K, Lambrechts D, Janssen G, Fazzi G, Verstreken P, Haigh J, Schiffers P, Rohrer H, Van der Linden A, De Mey J, Carmeliet P. Impaired autonomic regulation of resistance arteries in VEGF∂/∂ mice or upon VEGF-trap delivery. Circulation 2010; 122: 273-281. Storkebaum E, Leitao-Gonçalves R, Godenschwege T, Nangle L, Mejia M, Bosmans I, Ooms T, Jacobs A, Van Dijck P, Yang X-L, Schimmel P, Norga K, Timmerman V, Callaerts P and Jordanova A. Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy. Proc. Natl. Acad. Sci. USA 2009;106(28): 11782-11787. Storkebaum E, Lambrechts D, Dewerchin M, Oh H, Vermeulen K, Van Damme P, Man WY, Demol M, Wyns S, Manka D, Van Den Bosch L., Mertens N, Robberecht W, Conway EM, Collen D, Moons L and Carmeliet P. Treatment of an aggressive form of motoneuron degeneration by intracerebroventricular delivery of recombinant VEGF in ALS animal models. Nature Neuroscience 2005 Jan;8(1):85-92. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004 May 27;429(6990):413-7. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics 2003 Aug;34(4):383-94. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Dorpe JV, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genetics 2001 Jun;28(2):131-8. Full publication list: |
| Courses |
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Molecular and Cellular Neurobiology |
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Theme 3:
Development and lifelong plasticity
Theme 2:
Perception, Action and Decision-making
Research Group
Molecular Neurobiology
Principal Investigator
prof. dr. Erik Storkebaum
Group members:
Postdocs
dr. Natalia Mora Garcia
dr. María Landinez Macias
dr. Hannah Walgrave
PhD candidates
Marije Been
María Paz Menafra Martínez
Erik Slot
Anne Wienand
Research and education assistants
Emanuele Calia
dr. Eric Jansen
Pascal van Lith
(Update August 2023)