title: NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration.
abstract: In chronic degenerative syndromes, neuronal death occurs over long periods, during which cells progressively lose their axons and, ultimately, their cell bodies. Although apoptosis is recognized as a key event in neuronal death, the molecular mechanisms involved in CNS axons degeneration are poorly understood. Due to the highly polarized phenotypes of CNS neurons, the different neuronal subcompartments are likely to be targeted by light repetitive and localized aggression. Such locally initiated deleterious signal transduction pathways could theoretically spread through the cytoplasm. However, where axon-degenerative signals initiate, what these early signals are, and how they lead to axon degeneration are unanswered questions that limit our understanding of neurodegenerative diseases and our ability to identify novel therapeutic targets. Using a microfluidic culture device adapted to CNS primary neurons, allowing specific access to the axonal and somatodendritic compartments, we analyzed the molecular pathways involved in axonal degeneration of differentiated neurons. We show here that local application of proapoptotic stimuli on the somatodentritic compartment triggers a dying-back pattern involving caspase-dependent axonal degeneration. Using complementary pharmacological and genetic approaches, we further demonstrate that NAD(+) and grape wine polyphenols prevent axonal apoptosis and act via mitochondrial SirT3 activation in axons.
authors: 1Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Université Pierre et Marie Curie, 9 Quai St.-Bernard, Bât.B, 6ème étage, 75005 Paris, France. jean-michel.peyrin@upmc.fr.
authors: Sébastien
authors: S
authors: Magnifico
authors: Laure
authors: L
authors: Saias
authors: Bérangère
authors: B
authors: Deleglise
authors: Eric
authors: E
authors: Duplus
authors: Devrim
authors: D
authors: Kilinc
authors: Marie-Christine
authors: MC
authors: Miquel
authors: Jean-Louis
authors: JL
authors: Viovy
authors: Bernard
authors: B
authors: Brugg
authors: Jean-Michel
authors: JM
authors: Peyrin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D051379:Mice; D044085:Microfluidics; D009243:NAD / Q000494:pharmacology*; D000077185:Resveratrol; D056566:Sirtuin 3 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology
chemical_list: C525046:Sirt3 protein, mouse; D013267:Stilbenes; D009243:NAD; D020169:Caspases; D056566:Sirtuin 3; D000077185:Resveratrol
keywords: apoptosis; microfluidic; sirtuin