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.

ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity / Garone, M. G.; Birsa, N.; Rosito, M.; Salaris, F.; Mochi, M.; de Turris, V.; Nair, R. R.; Cunningham, T. J.; Fisher, E. M. C.; Morlando, M.; Fratta, P.; Rosa, A.. - In: COMMUNICATIONS BIOLOGY. - ISSN 2399-3642. - 4:1(2021), p. 1025. [10.1038/s42003-021-02538-8]

ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity

Garone M. G.
Primo
;
Rosito M.;Salaris F.;Mochi M.;de Turris V.;Morlando M.;Rosa A.
Ultimo
2021

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.
2021
FUS; iPSC; motoneuron; axon; GAP43; NRN1; HuD; FMR1
01 Pubblicazione su rivista::01a Articolo in rivista
ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity / Garone, M. G.; Birsa, N.; Rosito, M.; Salaris, F.; Mochi, M.; de Turris, V.; Nair, R. R.; Cunningham, T. J.; Fisher, E. M. C.; Morlando, M.; Fratta, P.; Rosa, A.. - In: COMMUNICATIONS BIOLOGY. - ISSN 2399-3642. - 4:1(2021), p. 1025. [10.1038/s42003-021-02538-8]
File allegati a questo prodotto
File Dimensione Formato  
Garone_ALS-related_2021.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 5.1 MB
Formato Adobe PDF
5.1 MB Adobe PDF
Garone_ALS-related_2021.pdf

accesso aperto

Tipologia: Altro materiale allegato
Licenza: Creative commons
Dimensione 10.18 MB
Formato Adobe PDF
10.18 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1567941
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 15
social impact