Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.
Bottom Line: 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.
Affiliation: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR 1142, Montpellier Cedex 5, France.Show MeSH
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Mentions: Expression of PABPN1-17ala with Mhc-Gal4 leads to progressive defects in wing position (wings up or down). At 18°C, abnormal wing position appears at day 3 of adulthood with less than 20% of individuals showing defects, and this percentage reaches 90% at day 6 (Chartier et al, 2006). We analyzed the effect of feeding OPMD larvae and adults with increasing concentrations of 6AP, ranging from 250 to 400 µM. Wing position defects were scored at day 6 of adulthood, when 90% of individuals show defects in the absence of the drug (Fig 2A). A dose-dependent beneficial effect of 6AP was visible. The strongest effect was obtained in the presence of 400 µM 6AP, the percentage of individuals with wing position defects decreased to 50%. An identical experiment performed in the presence of the control molecule 6APi showed that this molecule had no effect (Fig 2A). We found that 400 µM of 6AP was still beneficial, although to a lesser extent, when provided during larval stages only, or from third instar larval to adult stages (Supplementary Fig 3). We verified that the positive effect of 6AP did not result from reduced levels of PABPN1-17ala in thoracic muscles of individuals fed with 6AP (Fig 2B).
Affiliation: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR 1142, Montpellier Cedex 5, France.