C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.
Science
; 345(6201): 1192-1194, 2014 Sep 05.
Article
in En
| MEDLINE
| ID: mdl-25103406
An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted "RNA-only" repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proteins
/
DNA Repeat Expansion
/
Drosophila melanogaster
/
Frontotemporal Dementia
/
Amyotrophic Lateral Sclerosis
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Science
Year:
2014
Document type:
Article
Country of publication:
Estados Unidos