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Antiprion Drugs 6-aminophenanthridine and Guanabenz Reduce PABPN1 Toxicity and Aggregation in Oculopharyngeal Muscular Dystrophy

Antiprion Drugs 6-aminophenanthridine and Guanabenz Reduce PABPN1 Toxicity and Aggregation in Oculopharyngeal Muscular Dystrophy

Nicolas Barbezier, Aymeric Chartier, Yannick Bidet, Anja Buttstedt, Cécile Voisset, Hervé Galons, Marc Blondel, Elisabeth Schwarz, Martine Simonelig

EMBO Mol Med. 2011 Jan;3(1):35-49.

PMID: 21204267

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP832688	6-Aminophenanthridine		832-68-8	Price

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