title: Resveratrol delays Wallerian degeneration in a NAD(+) and DBC1 dependent manner.
abstract: Axonal degeneration is a central process in the pathogenesis of several neurodegenerative diseases. Understanding the molecular mechanisms that are involved in axonal degeneration is crucial to developing new therapies against diseases involving neuronal damage. Resveratrol is a putative SIRT1 activator that has been shown to delay neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Alzheimer, and Huntington's disease. However, the effect of resveratrol on axonal degeneration is still controversial. Using an in vitro model of Wallerian degeneration based on cultures of explants of the dorsal root ganglia (DRG), we showed that resveratrol produces a delay in axonal degeneration. Furthermore, the effect of resveratrol on Wallerian degeneration was lost when SIRT1 was pharmacologically inhibited. Interestingly, we found that knocking out Deleted in Breast Cancer-1 (DBC1), an endogenous SIRT1 inhibitor, restores the neuroprotective effect of resveratrol. However, resveratrol did not have an additive protective effect in DBC1 knockout-derived DRGs, suggesting that resveratrol and DBC1 are working through the same signaling pathway. We found biochemical evidence suggesting that resveratrol protects against Wallerian degeneration by promoting the dissociation of SIRT1 and DBC1 in cultured ganglia. Finally, we demonstrated that resveratrol can delay degeneration of crushed nerves in vivo. We propose that resveratrol protects against Wallerian degeneration by activating SIRT1 through dissociation from its inhibitor DBC1.
authors.affiliation: Department of Molecular and Cellular Biology, School of Veterinary-UdelaR., Av. A. Lasplaces 1550, CP 11600, Montevideo, Uruguay; Department of Protein and Nucleic Acids, IIBCE-MEC, Av. Italia 3318, CP 11600, Montevideo, Uruguay. Electronic address: acalliari@iibce.edu.uy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Calliari
authors.affiliation: Department of Protein and Nucleic Acids, IIBCE-MEC, Av. Italia 3318, CP 11600, Montevideo, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bobba
authors.affiliation: Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Escande
authors.affiliation: Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. Electronic address: chini.eduardo@mayo.edu.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009243:NAD / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000077185:Resveratrol; D012584:Sciatic Nerve / Q000473:pathology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use*; D013997:Time Factors; D014162:Transfection; D014855:Wallerian Degeneration / Q000188:drug therapy*
chemical_list: D000975:Antioxidants; C508515:DAZL protein, mouse; D016900:Neurofilament Proteins; D016601:RNA-Binding Proteins; D013267:Stilbenes; D009243:NAD; C051774:neurofilament protein H; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Axonal degeneration; DBC1; Resveratrol; SIRT1; Wallerian degeneration