Cross-talk between canonical Wnt signaling and the sirtuin-FoxO longevity pathway to protect against muscular pathology induced by mutant PABPN1 expression in C. elegans
| Autor: | J. Alex Parker, Bernard Brais, Hélène Catoire, Guy A. Rouleau, Matthieu Y. Pasco, Christian Neri |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Pathology
medicine.medical_specialty Mutant Poly(A)-Binding Proteins Cell survival lcsh:RC321-571 Animals Genetically Modified Longevity Pathway Glycogen Synthase Kinase 3 RNA interference medicine Animals Sirtuins Muscular dystrophy Caenorhabditis elegans Caenorhabditis elegans Proteins lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry beta Catenin Muscle Cells Glycogen Synthase Kinase 3 beta biology PABPN1 Wnt signaling pathway High Mobility Group Proteins Forkhead Transcription Factors medicine.disease Cell biology DNA-Binding Proteins Wnt Proteins Neurology Proteotoxicity Intracellular signaling Sirtuin Mutation C. elegans Cancer research biology.protein Mutant Proteins Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Neurobiology of Disease, Vol 38, Iss 3, Pp 425-433 (2010) |
| ISSN: | 1095-953X |
| Popis: | Developmental pathways may be play a role in adult cell survival. However, whether they interact with longevity/cell survival pathways to confer protection against disease-associated proteotoxicity remains largely unknown. We previously reported that the inhibition of key longevity modulators such as the deacetylase sir-2.1 /SIRT1 (Sir2) and its target daf-16 /FoxO protects transgenics nematodes from muscle cell decline and abnormal motility produced by the expression of mutant (polyalanine-expanded) PABPN1, the oculopharyngeal muscular dystrophy (OPMD) protein. Here, we report that canonical Wnt signaling ( i ) modulates muscular pathology in mutant PABPN1 nematodes, and ( ii ) cooperates with the Sir2-FoxO longevity pathway to confer protection against mutant PABPN1 toxicity at the cellular and behavioral levels. Mutant PABPN1 toxicity was modified by genes along the canonical Wnt pathway, several of which depend on daf-16 for activity. s-catenin and pop-1 /TCF RNAi suppressed the protection from mutant PABPN1 confered by loss-of-function mutations in sir-2.1 and daf-16 . Moreover, the aggravation of muscle cell pathology by increased sir-2.1 dosage was reversed by s-catenin and pop-1 RNAi. The chemical inhibition of GSK-3s, a repressor of s-catenin activity, protected against mutant PABPN1 toxicity in a daf-16 -dependent manner, which is consistent with a cross-talk between s-catenin signaling and Sir2-FoxO signaling in protecting from mutant PABPN1 toxicity. Our data reveal that canonical Wnt signaling and Sir2-FoxO signaling interact to modulate diseased muscle survival, and indicate that GSK-3s inhibitors and sirtuin inhibitors both have therapeutic potential for muscle protection in OPMD. |
| Databáze: | OpenAIRE |
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