13 Aug 2004. Lovers of red wine the world over may once again take comfort from the amazing powers of resveratrol, a grape-derived polyphenol that has been shown to extend lifespan in yeast, worms, and fruit flies, and which activates the deacetylase SIRT1, which extends lifespan of mammalian cells (see ARF related news story). In today’s Science, Jeffrey Milbrandt and colleagues at Washington University School of Medicine, St. Louis, report that Wallerian degeneration, the active process whereby neuronal axons are destroyed, is inhibited by resveratrol and its aide d’accompli, SIRT1. The results may have implications for the protection of neurons in Alzheimer’s and other neurodegenerative diseases in which synaptic and dendritic death is often the best correlate of cognitive decline (see Hashimoto and Masliah, 2003).
First author Toshiyuki Araki and colleagues made the connection between the deacetylase and axonal degeneration by studying a mutation in mice that causes slow Wallerian degeneration. The Wlds mutation is caused by a recombination event (see ARF related news story) that results in expression of a protein chimera comprising the N-terminal of Ufd2a (ubiquitin fusion degradation protein 2a) and a full length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1). Ufd2a was strongly touted as the business end of this chimera, given that the proteasome/ubiquitin system had previously been implicated in Wallerian degeneration (see ARF related news story). But when Araki introduced some extra Nmnat1 into normal neurons and then severed their axons, he found they were protected just as well as Wlds axons. In fact, 72 hours after separation, more than 90 percent of axons are still intact in both normal neurons expressing the extra Nmnat1, and in Wlds neurons. In contrast, only about 10 percent of normal axons survive the same insult. What’s more, Araki found that knocking down Ufd2a doesn’t help. In neurons treated with small interfering Ufd2a RNAs, axons were not protected. This finding dashes the theory that the Wlds chimera acts as a dominant-negative Ufd2a.
So where do resveratrol and SIRT1 enter the picture? Well, SIRT1 is NAD-dependent, and Nmnat1 is involved in NAD biosynthesis. To prove that NAD plays a role in slowing Wallerian degeneration, Araki mutated Nmnat1 amino acids that are essential for this activity, and sure enough, these mutants failed to protect axons. In fact, Araki found that just adding NAD prior to damaging the axons was sufficient to protect them.
Armed with this knowledge, the authors sought out proteins and pathways that may be influenced by changes in NAD levels, choosing to focus on protein deacetylases and polyADP-ribose polymerases (PARPs). When they tested for slow Wallerian degeneration in neurons treated with the deacetylase inhibitor sirtinol or the PARP inhibitor 3AB, they found that only sirtinol blocked the protective effects of NAD. Taking the next logical step, they individually knocked down all seven SIRT deacetylases and found that only loss of SIRT1 abolished the protective effects of NAD. Resveratrol, which activates SIRT1, was even better at protecting axons than was the nucleotide—0.1 mM of the polyphenol offered about the same protection as 1mM NAD.
In the broadest sense, these results link neurodegeneration with diet, basic metabolism, and longevity. “It is possible that the alteration of NAD levels by manipulation of the NAD biosynthetic pathway, Sir2 protein activity, or other downstream effectors will provide new therapeutic opportunities for the treatment of diseases involving axonopathy and neurodegeneration,” the authors write.
Antonio Bedalov and Julian Simon, from the Fred Hutchinson Cancer Research Center, Seattle, are equally optimistic. “The therapeutic implication of this finding is that it may be possible to design neuroprotective drugs that boost SIRT1 activity and prevent further neurodegeneration in diseases like AD and PD,” they write in an accompanying Science perspective.
In the meantime, maybe we should keep quaffing our favorite vintage.—Tom Fagan.
Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004 Aug 13;305:1010-1013. Abstract
Bedalov A, Simon JA. NAD to the rescue. Science. 2004 Aug 13;305:954-955. Abstract