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Defective protein translation as a pathogenic mechanism of peripheral neuropathy

Total Cost €


EC-Contrib. €






Project "CMTaaRS" data sheet

The following table provides information about the project.


Organization address
postcode: 6525 EZ

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Netherlands [NL]
 Total cost 2˙000˙000 €
 EC max contribution 2˙000˙000 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2017-COG
 Funding Scheme ERC-COG
 Starting year 2018
 Duration (year-month-day) from 2018-06-01   to  2023-05-31


Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 


 Project objective

Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking.

This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism.

In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model.

I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.


year authors and title journal last update
List of publications.
2019 Gina Picchiarelli, Maria Demestre, Amila Zuko, Marije Been, Julia Higelin, Stéphane Dieterlé, Marc-Antoine Goy, Moushami Mallik, Chantal Sellier, Jelena Scekic-Zahirovic, Li Zhang, Angela Rosenbohm, Céline Sijlmans, Amr Aly, Sina Mersmann, Inmaculada Sanjuan-Ruiz, Annemarie Hübers, Nadia Messaddeq, Marina Wagner, Nick van Bakel, Anne-Laurence Boutillier, Albert Ludolph, Clotilde Lagier-Tourenn
FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis
published pages: 1793-1805, ISSN: 1097-6256, DOI: 10.1038/s41593-019-0498-9
Nature Neuroscience 22/11 2020-02-18
2019 Thomas G. Moens, Teresa Niccoli, Katherine M. Wilson, Magda L. Atilano, Nicol Birsa, Lauren M. Gittings, Benedikt V. Holbling, Miranda C. Dyson, Annora Thoeng, Jacob Neeves, Idoia Glaria, Lu Yu, Julia Bussmann, Erik Storkebaum, Mercedes Pardo, Jyoti S. Choudhary, Pietro Fratta, Linda Partridge, Adrian M. Isaacs
C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A
published pages: 487-500, ISSN: 0001-6322, DOI: 10.1007/s00401-018-1946-4
Acta Neuropathologica 137/3 2020-02-18
2018 Moushami Mallik, Marica Catinozzi, Clemens B. Hug, Li Zhang, Marina Wagner, Julia Bussmann, Jonas Bittern, Sina Mersmann, Christian Klämbt, Hannes C.A. Drexler, Martijn A. Huynen, Juan M. Vaquerizas, Erik Storkebaum
Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity
published pages: 3947-3964, ISSN: 0021-9525, DOI: 10.1083/jcb.201802151
The Journal of Cell Biology 217/11 2020-02-18
2018 Marcel Naumann, Arun Pal, Anand Goswami, Xenia Lojewski, Julia Japtok, Anne Vehlow, Maximilian Naujock, René Günther, Mengmeng Jin, Nancy Stanslowsky, Peter Reinhardt, Jared Sterneckert, Marie Frickenhaus, Francisco Pan-Montojo, Erik Storkebaum, Ina Poser, Axel Freischmidt, Jochen H. Weishaupt, Karlheinz Holzmann, Dirk Troost, Albert C. Ludolph, Tobias M. Boeckers, Stefan Liebau, Susanne Petri,
Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-017-02299-1
Nature Communications 9/1 2020-02-18

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