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.

Hip flexion weakness is associated with impaired mobility in oculopharyngeal muscular dystrophy: A retrospective study with implications for trial design

“…Recent work on basic mechanisms of OPMD raises hopes for new treatments [41, 42]; however, a major obstacle to conducting clinical trials is lack of validated outcome measures to assess disease progression and treatment effects. Our study demonstrates that hip flexion weakness is statistically associated with impaired ambulation, and supports consideration of muscle strength as a surrogate endpoint in future trials.…”

The Antiprion Compound 6-Aminophenanthridine Inhibits the Protein Folding Activity of the Ribosome by Direct Competition

“…This notion was further reinforced by the discovery that a 6AP derivative called 6APi, in which the 6-amino group of 6AP is substituted with 2-butan-1-ol, was inactive in both the reversion of the prion phenotype in vivo and inhibition of PFAR in vitro (15). In a different context, PFAR was suggested to be involved in another amyloid-based disease, oculopharyngeal muscular dystrophy, which is an inherited myodegenerative disease caused by the aggregation of PABPN1 protein into amyloid fibers within the nucleus of muscle cells (18). Thus, even though the involvement of PFAR in prion processes has yet to be directly demonstrated, 6AP and guanabenz acetate constitute valuable tools for studying PFAR (19).…”

Pharmacological Modulation of the Retinal Unfolded Protein Response in Bardet-Biedl Syndrome Reduces Apoptosis and Preserves Light Detection Ability

“…We opted to inhibit the dephosphorylation of peIF2␣ using GBZ, a specific inhibitor of the eIF2␣-phosphatase, GADD34 (36). GBZ bears anti-prion activity (34) and was used to cure diseases linked to unfolded proteins conditions (51). Efficacy in reducing protein load in the photoreceptor was successfully demonstrated in the Ahi1 Ϫ/Ϫ mouse (14).…”