Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration

Abstract

Axonal degeneration is an active program of self-destruction that is observed in many physiological and pathological settings. In Wallerian degeneration slow (wlds) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wlds) composed of the ubiquitin assembly protein Ufd2a and the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme Nmnat1. We demonstrate that increased Nmnat activity is responsible for the axon-sparing activity of the Wlds protein. Furthermore, we demonstrate that SIRT1, a mammalian ortholog of Sir2, is the downstream effector of increased Nmnat activity that leads to axonal protection. These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…Indeed, potent therapeutic effects of resveratrol administration were reported in animal models of Alzheimer's disease and accelerated ageing [10,26,46], multiple sclerosis [47,48], Huntington's disease [9,49], Parkinson's disease [22,50], and even reducing peripheral axonal degeneration [51] or promoting functional recovery after traumatic spinal cord injury [23]. In this sense, resveratrol has been also reported to exert neuroprotection on in vitro models of ALS.…”

Nutrition, sirtuins and aging

“…It has been shown that increased dosage of key enzymes for mammalian NAD + -biosynthesis increase total cellular NAD + -levels and enhance the transcriptional regulation activity of a mouse Sir2 orthologue (Revollo et al, 2004). Such a strategy was shown also to protect injured axons in a SIRT1-dependent fashion in a Wallerian degeneration model (Araki et al, 2004). These studies suggest that mammalian Sir2 orthologues are sensitive to metabolic pathways that regulate the levels of NAD + .…”

“…2) (Wolkow et al, 2000;Hertweck et al, 2004). When central members of the insulin-/ IGF-1 pathway, such as DAF-2 or AGE-1 lose their function due to mutations, life span in C. elegans is increased two-fold as compared to wild-type animals (Kenyon et al, 1993;Araki et al, 2004). Animals with weak alleles of the age-1 and daf-2 genes can bypass dauer formation as a non-feeding, stress-resistant larval state that allows dispersal under adverse conditions, and turn into long-living adults in a daf-16 dependent manner (Kenyon et al, 1993;Barbieri et al, 2003 Recent studies show that sirtuins do interfere with the insulin/ IGF-1 signaling pathway.…”

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…Published evidence suggests that SirT1 prevents ageassociated diseases such as metabolic disorders (Picard et al, 2004;Kitamura et al, 2005;Moynihan et al, 2005;Bordone et al, 2006;Gerhart-Hines et al, 2007;Rodgers and Puigserver, 2007), neurodegenerative diseases (Araki et al, 2004;Parker et al, 2005;Chen et al, 2005a;Qin et al, 2006;Kim et al, 2007) and atherosclerosis . Accumulating evidence also point to SirT1 as having a function in cancer; however, inferences from the literature are that SirT1 has both oncogenic and tumor-suppressor activities.…”