Nmnat Delays Axonal Degeneration Caused by Mitochondrial and Oxidative Stress

“Mitochondrial dysfunction caused by mutations or toxic agents has been implicated in many neurodegenerative diseases, including those associated with axonal degeneration (Lin and Beal, 2006).”

“, DJ-1 and PINK-1) (Martin, 2006) and ingestion of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), an inhibitor of mitochondrial complex I (Langston et al., 1983; Betarbet et al., 2000).”

“…Parkinson’s disease (PD), which can be associated with mutations in mitochondria-associated proteins (e.g., DJ-1 and PINK-1) (Martin, 2006) and ingestion of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), an inhibitor of mitochondrial complex I (Langston et al., 1983; Betarbet et al., 2000).”

“…chronic rotenone model of PD, which more closely mimics the degenerative progression observed in PD patients, because this model only works in rats (Hornykiewicz, 1966; Betarbet et al., 2000; Richter et al., 2007); however, our results suggest that increasing Nmnat expression in this model may…”

“The suppression of ROS accumulation by Nmnat proteins is reminiscent of that observed in cells treated with antioxidants, whose utility in preventing axonal degeneration secondary to mitochondrial inhibition has been suggested by others (Sherer et al., 2003, 2007; Testa et al., 2005).”

“…axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam et al., 2003; Araki et al., 2004; Gillingwater et al., 2004; Mi et al., 2005; Sasaki et al., 2006; Zhai et al., 2006).”

“These changes are followed by calpain activation and eventual axonal protein degradation (Coleman, 2005).”

“For example, complex I inhibition and oxidative damage to mitochondrial proteins have been observed in brains of PD patients, changes that can be replicated by treatment of isolated mitochondria with rotenone (Keeney et al., 2006).”

“…of PD (Sherer et al., 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al., 1998, 2004; Priyadarshi et al., 2000, 2001; Ascherio et al., 2006; Brown et al., 2006).”

“…of ROS, other sources of ROS production include membrane-bound NADPH-oxidase, a source of oxidative products induced in neurons by signaling intermediates, and xanthine oxidase, which produces ROS in neurons in response to hypoxia and glucose deprivation (Ibi et al., 2006; Abramov et al., 2007).”

“Studies of the Wld mutant mouse, which exhibits slow axonal Wallerian degeneration in response to nerve injury, have led to the conclusion that axonal degeneration, like apoptosis, is an active process (Lunn et al., 1989; Raff et al., 2002).”

“One model of axonal degeneration derives from studies of anoxic injury to axons, which leads to mitochondrial failure, decreased levels of ATP, reduced Na /K ATPase activity, and increased axonal Na and Ca 2 (Stys et al., 1992).”

“Studies of the Wld mutant mouse, which exhibits slow axonal Wallerian degeneration in response to nerve injury, have led to the conclusion that axonal degeneration, like apoptosis, is an active process (Lunn et al., 1989; Raff et al., 2002).”

“Interestingly, the production and usage of NAD and its metabolites can play important roles in antioxidant responses (Mack et al., 2001).”

“It is generally accepted that environmental factors play an important role in the pathogenesis of PD (Sherer et al., 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al.,…”

“Many studies in both rodents and Drosophila have confirmed these results (Hoopfer et al., 2006; Macdonald et al., 2006; Zhai et al., 2006), whereas other investigators have suggested the Ube4b fragment may modulate the Nmnat protective effect (Wang et al., 2005; Conforti et al., 2007).”

“adenine dinucleotide (NAD ) (Araki et al., 2004; Berger et al., 2005), although recent studies in Drosophila neurodegeneration have suggested that additional Nmnat activities may also be important for synaptic protection (Zhai et al.”

“…of PD (Sherer et al., 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al., 1998, 2004; Priyadarshi et al., 2000, 2001; Ascherio et al., 2006; Brown et al., 2006).”

“, 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al., 1998, 2004; Priyadarshi et al., 2000, 2001; Ascherio et al., 2006; Brown et al., 2006).”

“, 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al., 1998, 2004; Priyadarshi et al., 2000, 2001; Ascherio et al., 2006; Brown et al., 2006).”

“, 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al., 1998, 2004; Priyadarshi et al., 2000, 2001; Ascherio et al., 2006; Brown et al., 2006).”

“It results in a host of cellular abnormalities, including decreased ATP synthesis, disrupted mitochondrial fusion and transport, and the increased generation of reactive oxygen species (ROS) (Lin and Beal, 2006; Baloh et al., 2007).”

“Many studies in both rodents and Drosophila have confirmed these results (Hoopfer et al., 2006; Macdonald et al., 2006; Zhai et al., 2006), whereas other investigators have suggested the Ube4b fragment may modulate the Nmnat protective effect (Wang et al., 2005; Conforti et al., 2007).”

“The suppression of ROS accumulation by Nmnat proteins is reminiscent of that observed in cells treated with antioxidants, whose utility in preventing axonal degeneration secondary to mitochondrial inhibition has been suggested by others (Sherer et al., 2003, 2007; Testa et al., 2005).”

“This would imply, as suggested by others, that ROS-stimulated processes could be a point of convergence for multiple pathways that culminate in axonal degeneration (Arundine et al., 2004; Alexandre et al., 2006; Holtz et al., 2006).”

“The suppression of ROS accumulation by Nmnat proteins is reminiscent of that observed in cells treated with antioxidants, whose utility in preventing axonal degeneration secondary to mitochondrial inhibition has been suggested by others (Sherer et al., 2003, 2007; Testa et al., 2005).”

“TTX treatment should serve to increase neuro- nal ATP levels, because it inhibits the influx of sodium and negates the need to expend ATP for maintaining axonal membrane potential via the Na /K ATPase (Stys, 2004).”

“…axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam et al., 2003; Araki et al., 2004; Gillingwater et al., 2004; Mi et al., 2005; Sasaki et al., 2006; Zhai et al., 2006).”

“Many studies in both rodents and Drosophila have confirmed these results (Hoopfer et al., 2006; Macdonald et al., 2006; Zhai et al., 2006), whereas other investigators have suggested the Ube4b fragment may modulate the Nmnat protective effect (Wang et al., 2005; Conforti et al., 2007).”

“and the full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) protein (Conforti et al., 2000).”

“…of PD (Sherer et al., 2002a); in particular, there is a strong association between PD and exposure to pesticides, including many that inhibit mitochondrial complex I (Semchuk et al., 1992; Gorell et al., 1998, 2004; Priyadarshi et al., 2000, 2001; Ascherio et al., 2006; Brown et al., 2006).”

“Results Rotenone treatment of DRG neurons results in axonal degeneration The expression of Wld, Nmnat1, or Nmnat3 in neurons protects against axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam…”

“These deficits could be rescued by expression of superoxide dismutase or treatment with the antioxidant vitamin E, suggesting that ROS was responsible for the damage (Wang et al., 2006).”

“It is possible that rotenone does cause small changes in the mitochondrial membrane potential, but the physiological significance of small changes in mitochondrial membrane potential is unclear (Nicholls, 2004; Nicholls et al., 2007).”

“…axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam et al., 2003; Araki et al., 2004; Gillingwater et al., 2004; Mi et al., 2005; Sasaki et al., 2006; Zhai et al., 2006).”

“Results Rotenone treatment of DRG neurons results in axonal degeneration The expression of Wld, Nmnat1, or Nmnat3 in neurons protects against axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam…”

“…effects, such as DNA damage; oxidation of proteins, which leads to their subsequent inhibition; and oxidation of lipids, which creates toxic products, including 4-hydroxynonenal (Geller et al., 2001; Sherer et al., 2002b; Duarte et al., 2005; Keeney et al., 2006; Ramachandiran et al., 2007).”

“Interestingly, studies with the acute 6-OHDA and MPTP rodent PD models showed that the Wld mutation provided robust protection against TH fiber loss but little or no protection of dopaminergic neuronal cell bodies (Sajadi et al., 2004; Hasbani and O’Malley, 2006).”

“Many studies in both rodents and Drosophila have confirmed these results (Hoopfer et al., 2006; Macdonald et al., 2006; Zhai et al., 2006), whereas other investigators have suggested the Ube4b fragment may modulate the Nmnat protective effect (Wang et al., 2005; Conforti et al., 2007).”

“This would imply, as suggested by others, that ROS-stimulated processes could be a point of convergence for multiple pathways that culminate in axonal degeneration (Arundine et al., 2004; Alexandre et al., 2006; Holtz et al., 2006).”

“This would imply, as suggested by others, that ROS-stimulated processes could be a point of convergence for multiple pathways that culminate in axonal degeneration (Arundine et al., 2004; Alexandre et al., 2006; Holtz et al., 2006).”

“Excessive ROS production has multiple detrimental effects, such as DNA damage; oxidation of proteins, which leads to their subsequent inhibition; and oxidation of lipids, which creates toxic products, including 4-hydroxynonenal (Geller et al., 2001; Sherer et al., 2002b; Duarte et al., 2005; Keeney et al., 2006; Ramac…”

“Results Rotenone treatment of DRG neurons results in axonal degeneration The expression of Wld, Nmnat1, or Nmnat3 in neurons protects against axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam…”

“Mitochondrial dysfunction is often accompanied by a decrease in mitochondrial membrane potential (Nicholls, 2004), and others have suggested that dissipation of mitochondrial membrane potential precedes axonal degeneration and that the degeneration can be blocked if the mitochondrial membrane potential is preserved (I…”

“…was not directly addressed in that study; however, the results are consistent with the idea that moderate mitochondrial inhibition causes damage primarily via excess ROS production rather than through abnormalities associated with energetic deficits (i.e., decreased ATP) (Bao et al., 2005).”

“…of Wlds, Nmnat1, or Nmnat3 in neurons protects against axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam et al., 2003; Araki et al., 2004; Gillingwater et al., 2004; Mi…”

“Nmnat3 inhibits ROS accumulation in vincristine-treated neurons In addition to their axonal protective effects after mechanical injury or mitochondrial inhibition, Wld s and Nmnat proteins protect against vincristine-mediated axonal degeneration (Wang et al., 2001b; Araki et al., 2004).”

“Mitochondrial dysfunction is often accompanied by a decrease in mitochondrial membrane potential (Nicholls, 2004), and others have suggested that dissipation of mitochondrial membrane potential precedes axonal degeneration and that the degeneration can be blocked if the mitochondrial membrane potential is preserved (I…”

“Protection of oxidant-mediated axonal damage by Nmnat suggested that it might act via increasing neuronal expression of antioxidant proteins, including superoxide dismutase, glutathione peroxidase, and/or catalase (Thiruchelvam et al., 2005; Fernandez-Gomez et al., 2006; Jung et al., 2007).”

“Indeed, antioxidants provide protection for dopaminergic neurons in the MPTP, 6-OHDA, rotenone, and genetic models of PD in vivo and in vitro (Schulz et al., 1995; Matthews et al., 1999; Bahat-Stroomza et al., 2005; Testa et al., 2005; Wang et al., 2006).”

“Recent studies have shown that vincristine toxicity in cancer cells may be mediated by ROS and that treatment with antioxidants can inhibit vincristine-induced cell death (Groninger et al., 2002; Tsai et al., 2007).”

“…mimics the degenerative progression observed in PD patients, because this model only works in rats (Hornykiewicz, 1966; Betarbet et al., 2000; Richter et al., 2007); however, our results suggest that increasing Nmnat expression in this model may rescue axonal function and thereby prevent…”

“The association of mitochondrial dysfunction with neurodegenerative diseases is perhaps strongest in Parkinson’s disease (PD), which can be associated with mutations in mitochondria-associated proteins (e.g., DJ-1 and PINK-1) (Martin, 2006) and ingestion of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), an inhib…”

“…of ROS, other sources of ROS production include membrane-bound NADPH-oxidase, a source of oxidative products induced in neurons by signaling intermediates, and xanthine oxidase, which produces ROS in neurons in response to hypoxia and glucose deprivation (Ibi et al., 2006; Abramov et al., 2007).”

“Excessive ROS production has multiple detrimental effects, such as DNA damage; oxidation of proteins, which leads to their subsequent inhibition; and oxidation of lipids, which creates toxic products, including 4-hydroxynonenal (Geller et al., 2001; Sherer et al., 2002b; Duarte et al., 2005; Keeney et al., 2006; Ramac…”

“Nmnat3 inhibits ROS accumulation in vincristine-treated neurons In addition to their axonal protective effects after mechanical injury or mitochondrial inhibition, Wld s and Nmnat proteins protect against vincristine-mediated axonal degeneration (Wang et al., 2001b; Araki et al., 2004).”

“Indeed, antioxidants provide protection for dopaminergic neurons in the MPTP, 6-OHDA, rotenone, and genetic models of PD in vivo and in vitro (Schulz et al., 1995; Matthews et al., 1999; Bahat-Stroomza et al., 2005; Testa et al., 2005; Wang et al., 2006).”

“…axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam et al., 2003; Araki et al., 2004; Gillingwater et al., 2004; Mi et al., 2005; Sasaki et al., 2006; Zhai et al., 2006).”

“Several studies have indicated that increased ROS levels, and not the loss of ATP, are the proximal causes for neuronal death induced by mitochondrial inhibition (Sherer et al., 2003; Watabe and Nakaki, 2006).”

“However, consistent with other studies with rotenone (JohnsonCadwell et al., 2007; Marella et al., 2007), we did not observe a collapse of mitochondrial membrane potential after rotenone treatment (6 h) at a time when rotenone-induced increases in ROS are already observed (Fig.”

“It does not appear that transcriptional changes for previously identified antioxidant genes are involved (Gillingwater et al., 2006).”

“One possibility is that Nmnat proteins increase NAD availability without increasing NADH breakdown via oxidation, thus providing more NADH for conversion to NADPH, a cofactor for many ROS-scavenging enzymes (Mazzio and Soliman, 2003).”

“Protection of oxidant-mediated axonal damage by Nmnat suggested that it might act via increasing neuronal expression of antioxidant proteins, including superoxide dismutase, glutathione peroxidase, and/or catalase (Thiruchelvam et al., 2005; Fernandez-Gomez et al., 2006; Jung et al., 2007).”

“Recent studies have shown that vincristine toxicity in cancer cells may be mediated by ROS and that treatment with antioxidants can inhibit vincristine-induced cell death (Groninger et al., 2002; Tsai et al., 2007).”

“Other insults not directly linked to mitochondrial dysfunction, including taxol, vincristine, and mechanical injury, also induce ROS and neurodegeneration (Hall, 1987; Groninger et al., 2002; Arundine et al., 2004; Alexandre et al., 2006; Holtz et al., 2006; Tsai et al., 2007).”

“Indeed, antioxidants provide protection for dopaminergic neurons in the MPTP, 6-OHDA, rotenone, and genetic models of PD in vivo and in vitro (Schulz et al., 1995; Matthews et al., 1999; Bahat-Stroomza et al., 2005; Testa et al., 2005; Wang et al., 2006).”

“…luciferase-based ATP assay (Promega, Madison, WI), where ATP is expressed as a percentage of control based on arbitrary units of luminescence and then converted to micromolar ATP based on a standard curve (n 6 wells per condition; results are from two independent experiments) (Chang et al., 2003).”

“It has been hypothesized that increasing NAD concentration via NMNAT1 and the consequent SIRT1 activation might play a role (212, 218, 219).”

“…subcellular localization studies have found substantial amounts of WldS within the mitochondrial matrix where it may enhance ATP synthesis (Yahata et al., 2009), prevent free radical formation (Press and Milbrandt, 2008), and/or maintain mitochondrial membrane potential (Ikegami and Koike, 2003).”

“, 2001), fails to delay axon degeneration after axotomy (George et al., 1995; Press and Milbrandt, 2008), suggesting that Na entry is not the primary signal to trigger Ca influx, or does not lead to sufficient Ca entry to initiate Wallerian axon de­ generation.”

“One proposal is that Nmnat activity decreases reactive oxygen species in mitochondria because it protects axons from rotenone-induced damage without restoring normal ATP levels (Press & Milbrandt 2008).”