Garone, MG;
Birsa, N;
Rosito, M;
Salaris, F;
Mochi, M;
de Turris, V;
Nair, RR;
... Rosa, A; + view all
(2021)
ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity.
Communications Biology
, 4
, Article 1025. 10.1038/s42003-021-02538-8.
(In press).
Preview |
Text
Cosentino2021_Article_AMultinationalConsensusOnDysph.pdf - Published Version Download (892kB) | Preview |
Abstract
Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3’UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS.
| Type: | Article |
|---|---|
| Title: | ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s42003-021-02538-8 |
| Publisher version: | http://dx.doi.org/10.1038/s42003-021-02538-8 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Amyotrophic lateral sclerosis, Induced pluripotent stem cells, Mechanisms of disease, Motor neuron, RNA metabolism |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10134348 |
Archive Staff Only
 |
View Item |
