Nmnat exerts neuroprotective effects in dendrites and axons

Abstract

Dendrites can be maintained for extended periods of time after they initially establish coverage of their receptive field. The long-term maintenance of dendrites underlies synaptic connectivity, but how neurons establish and then maintain their dendritic arborization patterns throughout development is not well understood. Here, we show that the NAD synthase Nicotinamide mononucleotide adenylyltransferase (Nmnat) is cell-autonomously required for maintaining type-specific dendritic coverage of Drosophila dendritic arborization (da) sensory neurons. In nmnat heterozygous mutants, dendritic arborization patterns of class IV da neurons are properly established before increased retraction and decreased growth of terminal branches lead to progressive defects in dendritic coverage during later stages of development. Although sensory axons are largely intact in nmnat heterozygotes, complete loss of nmnat function causes severe axonal degeneration, demonstrating differential requirements for nmnat dosage in the maintenance of dendritic arborization patterns and axonal integrity. Overexpression of Nmnat suppresses dendrite maintenance defects associated with loss of the tumor suppressor kinase Warts (Wts), providing evidence that Nmnat, in addition to its neuroprotective role in axons, can function as a protective factor against progressive dendritic loss. Moreover, motor neurons deficient for nmnat show progressive defects in both dendrites and axons. Our studies reveal an essential role for endogenous Nmnat function in the maintenance of both axonal and dendritic integrity and present evidence of a broad neuroprotective role for Nmnat in the central nervous system.

Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

“…This also extends to a recent Tau neurotoxicity model in Drosophila where non-enzyme Nmnat also has a neuroprotective effect (Ali et al, 2012). Another recent report suggest Nmnat also has a role in dendritic maintenance that is enzyme-independent (Wen et al, 2011). All these studies put together suggest a growing involvement of non-enzyme Nmnat function in various neuropathological conditions that is intimately linked to neuronal maintenance and stability.…”

“…Also, while in many neurodegenerative paradigms the Nmnat enzyme activity is essential, it is unclear how the NAD + pathway contributes to axonal protection (Araki et al, 2004;Wang et al, 2005;Kaneko et al, 2006;Conforti et al, 2007;Avery et al, 2009;Sasaki et al, 2009;Coleman and Freeman, 2010). Furthermore, some studies suggest Nmnat neuroprotective functions are enzyme-independent (Zhai et al, 2006;Zhai et al, 2008;Wen et al, 2011). To date, the relationship between Wld S function(s) and axon-neuronal damage and repair also remains unclear, although recent data suggest Wld S -Nmnat regulation of mitochondrial motility and calcium buffering functions may underlie key neuroprotective responses to physical injury in Drosophila and mouse axons (Avery et al, 2012).…”

“…However, apart from Drosophila Nmnat (Wen et al, 2011;Fang et al, 2012), currently only mouse Nmnat2 has an endogenous role in promoting axonal stability Hicks et al, 2012). It is important to note, beyond their neuronal roles, Nmnats also have obligate roles in NAD + metabolism and multiple cellular processes across species (Zhai et al, 2009;Lin et al, 2010).…”

The NAD+ salvage pathway modulates cancer cell viability via p73

“…Accumulating evidence suggests that elements of the NAD + salvage pathway have important roles in maintaining neuronal health, 35,36 whereas separate and unrelated studies have reported that p73 is a major regulator of neural stem cell maintenance and neurodegeneration during aging and Alzheimer's disease. 37,38 In view of the observations from the present study, it would seem logical to conjecture that these are related events, with p73 as the executioner regulated by the NAD + salvage pathway.…”

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

“…This hypothesis is supported by the observation that NMNAT3 upregulation in the fly brain is capable of enhancing the life span of flies in response to oxidative stress 21. Similarly, NMNAT3 overexpression reduced the degeneration of DRG axons after exposure to exogenous toxic oxidants such as rotenone and hydrogen peroxide,30 and increases in Drosophila NMNAT prevented hypoxia‐induced degeneration of neuronal dendrites 20, 36. In this study, we also find that NMNAT3‐overexpressing mice have lower mortality during the acute phase of H‐I compared to their littermate controls (Fig.…”