Donders Institute for Brain, Cognition and Behaviour
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Theme 3: Development and lifelong plasticity

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

Research grants

2022 - NWO-ENW-M grant (360,000€)

2022 - Muscular Dystrophy Association (MDA) grant (300,000$)

2022 - Prinses Beatrix Spierfonds grant (280,000€)

2022 - Dutch ALS Association grant (167,000€) 

2021 - AFM-Telethon grant together with Luc Dupuis: 152,000€ (45,000€ for my lab)

2021 - ARSLA grant together with Luc Dupuis: 192,000€ (45,000€ for my lab)

2020 - Radala Foundation for ALS Research: Advanced Research Grant. 200,000 CHF

2017 – ERC consolidator grant “Defective protein translation as a pathogenic mechanism of peripheral neuropathy”. 2,000,000€

2017 – Coordinator of JPND network grant “Altered mRNA translation as a pathogenic mechanism across neurodegenerative diseases”. 1,832,000€ (341,000€ for our lab)

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
2010 - Frick Foundation Award for ALS research.

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

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.

Picchiarelli G, Demestre M, Zuko A, Been M, Higelin J, Dieterlé S, Goy M-A, Mallik M, Sellier C, Scekic-Zahirovic J, Zhang L, Rosenbohm A, Sijlmans C, Aly A, Mersmann S, Sanjuan-Ruiz I, Hübers A, Messaddeq N, Wagner M, van Bakel N, Boutillier A-L, Ludolph A, Lagier-Tourenne C, Boeckers T, Dupuis L, Storkebaum E. FUS-mediated transcriptional regulation of acetylcholine receptor at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.Nature Neuroscience, 2019; doi: 10.1038/s41593-019-0498-9.

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, El Oussini H, Mersmann S, Drenner K, Wagner M, Sun Y, Allmeroth K, Dieterlé S, Sinniger J, Dirrig-Grosch S, René F, Dormann D, Haass C, Ludolph A, Lagier-Tourenne C, Storkebaum E*, Dupuis L*. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta Neuropathologica 2017, 133(6): 887-906. *corresponding authors.

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:
http://www.researcherid.com/rid/B-5389-2017

Courses

Molecular and Cellular Neurobiology
Translational Neuroscience Minor

Links

Curriculum Vitae (pdf, 267 kB)

https://www.ru.nl/molecularneurobiology/


Back to:
Theme 3:
Development and lifelong plasticity

Theme 2:
Perception, Action and Decision-making
Donders

Research Group

Molecular Neurobiology

Principal Investigator
prof. dr. Erik Storkebaum

Group members:

Postdocs
dr. Natalia Mora Garcia
dr. María Landinez Macias

PhD candidates
Marije Been
María Paz Menafra Martínez
Erik Slot
Anne Wienand

Technician
Nick van Bakel



(Update November 2022)