title: Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1.
abstract: Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases.
authors.affiliation: INSERM, Laboratory of Neuronal Cell Biology and Pathology, Center for Psychiatry and Neuroscience UMR 894, University of Paris Descartes, Equipe d'accueil 4059, 75014 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Catoire
authors.forename: Matthieu Y
authors.initials: MY
authors.lastname: Pasco
authors.forename: Aida
authors.initials: A
authors.lastname: Abu-Baker
authors.forename: Sébastien
authors.initials: S
authors.lastname: Holbert
authors.forename: Cendrine
authors.initials: C
authors.lastname: Tourette
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
authors.forename: Christian
authors.initials: C
authors.lastname: Néri
mesh_terms: D055372:AMP-Activated Protein Kinases; D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D001549:Benzamides / Q000494:pharmacology; D019556:COS Cells; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D002522:Chlorocebus aethiops; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006657:Histones / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes; D009132:Muscles / Q000378:metabolism / Q000503:physiopathology; D039141:Muscular Dystrophy, Oculopharyngeal / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009284:Naphthols / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D006657:Histones; D009097:Multienzyme Complexes; D009284:Naphthols; C111580:PAIP1 protein, human; D010448:Peptide Initiation Factors; D010455:Peptides; D016601:RNA-Binding Proteins; D013267:Stilbenes; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C439060:sirtinol; C019529:polyalanine; D017346:Protein Serine-Threonine Kinases; C510541:AAK-2 protein, C elegans; D055372:AMP-Activated Protein Kinases; C507014:SIR-2.1 protein, C elegans; D037761:Sirtuins; D000077185:Resveratrol