| Autor: |
Brunet, Marie A., Jacques, Jean-Francois, Nassari, Sonya, Tyzack, Giulia E., McGoldrick, Philip, Zinman, Lorne, Jean, Steve, Robertson, Janice, Patani, Rickie, Roucou, Xavier |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| DOI: |
10.1101/848580 |
| Popis: |
A bstract Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We discovered an altORF nested in the FUS CDS encoding a conserved protein, altFUS. We thus demonstrate the dual-coding nature of the Amyotrophic Lateral Sclerosis (ALS)-associated FUS gene. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons of healthy controls and ALS patients. AltFUS inhibits autophagy, a pathological hallmark presently and incorrectly attributed to the FUS protein. AltFUS is pivotal in two other pathological hallmarks: loss of mitochondrial membrane potential and accumulation of FUS/TDP-43 cytoplasmic aggregates. Suppression of altFUS expression in a FUS -ALS Drosophila model protects against neurodegeneration. Thus, wild-type altFUS is essential for ALS-like phenotypes arising from mutated FUS. Some mutations found in ALS patients are overlooked because of their synonymous effect on the FUS protein, yet we showed they exert a deleterious effect via their missense consequence on the overlapping altFUS protein. These findings suggest that both proteins, FUS and altFUS, are involved in the aetiology and pathological hallmarks of ALS. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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