Open Close
Reference
Citation
Barbezier, N., Chartier, A., Bidet, Y., Buttstedt, A., Voisset, C., Galons, H., Blondel, M., Schwarz, E., Simonelig, M. (2011). Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.  EMBO Mol. Med. 3(1): 35--49.
FlyBase ID
FBrf0212644
Publication Type
Research paper
Abstract

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules.

PubMed ID
PubMed Central ID
PMC3044817 (PMC) (EuropePMC)
Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    EMBO Mol. Med.
    Title
    EMBO molecular medicine
    ISBN/ISSN
    1757-4676 1757-4684
    Data From Reference
    Aberrations (1)
    Alleles (3)
    Genes (3)
    Human Disease Models (1)
    Transgenic Constructs (2)