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Human Molecular Genetics Advance Access originally published online on April 7, 2008
Human Molecular Genetics 2008 17(14):2108-2117; doi:10.1093/hmg/ddn109
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1

Hélène Catoire1,2, Matthieu Y. Pasco1,2,3, Aida Abu-Baker3, Sébastien Holbert1,2, Cendrine Tourette1,2, Bernard Brais3, Guy A. Rouleau3, J. Alex Parker1,2 and Christian Néri1,2,*

1 INSERM, Laboratory of Neuronal Cell Biology and Pathology, Center for Psychiatry and Neuroscience UMR 894 2 University of Paris Descartes, Equipe d'accueil 4059, 75014 Paris, France 3 Centre de Recherche du CHUM, University of Montreal, Montreal, Quebec, Canada H2L 4M1

* To whom correspondence should be addressed. Tel: +33 140788652; Fax: +33 145807293; Email: neri{at}broca.inserm.fr

Received January 9, 2008; Accepted April 2, 2008

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.


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