TY - JOUR
T1 - Resveratrol delays Wallerian degeneration in a NAD+ and DBC1 dependent manner
AU - Calliari, Aldo
AU - Bobba, Natalia
AU - Escande, Carlos
AU - Chini, Eduardo N.
N1 - Funding Information:
The authors gratefully acknowledge Dr. Angel Caputi (Department of Integrative and Computational Neuroscience, IIBCE) for help with the electrophysiological recordings and data analysis, and Berthil FF Clasen (Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark) for manuscript editing. This research was supported in part by the Human Resources Program of the University of the Republic (CSIC-UdelaR, Uruguay) and by the Mayo Clinic .
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
KW - Axonal degeneration
KW - DBC1
KW - Resveratrol
KW - SIRT1
KW - Wallerian degeneration
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U2 - 10.1016/j.expneurol.2013.11.013
DO - 10.1016/j.expneurol.2013.11.013
M3 - Article
AN - SCOPUS:84888860989
SN - 0014-4886
VL - 251
SP - 91
EP - 100
JO - Experimental Neurology
JF - Experimental Neurology
ER -