Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.

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.

• Authors: Nicolas Barbezier, Aymeric Chartier, Yannick Bidet, Anja Buttstedt, Cécile Voisset, Hervé Galons, Marc Blondel, Elisabeth Schwarz, Martine Simonelig
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 3 Issue 1 Pg. 35-49 (Jan 2011) ISSN: 1757-4684 [Electronic] England
• PMID: 21204267 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 EMBO Molecular Medicine.

Chemical References

• 6-aminophenanthridine
• Phenanthridines
• Poly(A)-Binding Protein II
• RNA, Ribosomal
• Guanabenz

Topics

• Animals
• Drosophila (growth & development, metabolism)
• Guanabenz (therapeutic use)
• Larva (metabolism)
• Muscular Dystrophy, Oculopharyngeal (drug therapy, metabolism)
• Phenanthridines (therapeutic use)
• Phenotype
• Poly(A)-Binding Protein II (metabolism)
• Prion Diseases (drug therapy)
• Protein Folding
• RNA, Ribosomal (metabolism)