Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity

Yan, Tingting; Yan, Feng; Zheng, Jinxing; Ge, Xinjian; Zhang, Yi; Wu, Dongmei; Zhao, Jing; Zhai, Qiwei

doi:10.1016/j.neuint.2009.09.007

Cited by 83 publications

(100 citation statements)

References 36 publications

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“…Like Wld S , each can delay Wallerian degeneration when overexpressed (Sasaki et al, 2006;Yan et al, 2010), but depletion of NMNAT2 alone causes spontaneous neurite degeneration, which endogenous NMNAT1 and NMNAT3 cannot prevent (Gilley and Coleman, 2010). Loss of short-lived NMNAT2 has therefore been proposed as a natural trigger for Wallerian and related, Wallerian-like axon degeneration, with Wld S directly substituting for NMNAT2 loss in compromised axons because it is relatively much more stable and shares critical NMNAT activity (Gilley and Coleman, 2010).…”

Section: Introductionmentioning

confidence: 99%

Rescue of Peripheral and CNS Axon Defects in Mice Lacking NMNAT2

Gilley

Adalbert

Yu³

et al. 2013

J. Neurosci.

107

163

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NMNAT2 is an NADϩ -synthesizing enzyme with an essential axon maintenance role in primary culture neurons. We have generated an Nmnat2 gene trap mouse to examine the role of NMNAT2 in vivo. Homozygotes die perinatally with a severe peripheral nerve/axon defect and truncated axons in the optic nerve and other CNS regions. The cause appears to be limited axon extension, rather than dying-back degeneration of existing axons, which was previously proposed for the NMNAT2-deficient Blad mutant mouse. Neurite outgrowth in both PNS and CNS neuronal cultures consistently stalls at 1-2 mm, similar to the length of truncated axons in the embryos. Crucially, this suggests an essential role for NMNAT2 during axon growth. In addition, we show that the Wallerian degeneration slow protein (Wld S ), a more stable, aberrant NMNAT that can substitute the axon maintenance function of NMNAT2 in primary cultures, can also correct developmental defects associated with NMNAT2 deficiency. This is dose-dependent, with extension of life span to at least 3 months by homozygous levels of Wld S the most obvious manifestation. Finally, we propose that endogenous mechanisms also compensate for otherwise limiting levels of NMNAT2. This could explain our finding that conditional silencing of a single Nmnat2 allele triggers substantial degeneration of established neurites, whereas similar, or greater, reduction of NMNAT2 in constitutively depleted neurons is compatible with normal axon growth and survival. A requirement for NMNAT2 for both axon growth and maintenance suggests that reduced levels could impair axon regeneration as well as axon survival in aging and disease.

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Section: Introductionmentioning

confidence: 99%

Rescue of Peripheral and CNS Axon Defects in Mice Lacking NMNAT2

Gilley

Adalbert

Yu³

et al. 2013

J. Neurosci.

107

163

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“…Studies in mammalian neurons have also shown that overexpression of NMNAT protects against injury-or stress-induced axonal degeneration (17)(18)(19)(20). The neuroprotective function of NMNAT is in part mediated through its chaperone activity independent of its NAD synthesis function (15) …”

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confidence: 99%

Nicotinamide Mononucleotide Adenylyltransferase Is a Stress Response Protein Regulated by the Heat Shock Factor/Hypoxia-inducible Factor 1α Pathway

Ali

McCormack

Darr

et al. 2011

Journal of Biological Chemistry

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Stress responses are cellular processes essential for maintenance of cellular integrity and defense against environmental and intracellular insults. Neurodegenerative conditions are linked with inadequate stress responses. Several stress-responsive genes encoding neuroprotective proteins have been identified, and among them, the heat shock proteins comprise an important group of molecular chaperones that have neuroprotective functions. However, evidence for other critical stressresponsive genes is lacking. Recent studies on the NAD synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) have uncovered a novel neuronal maintenance and protective function against activity-, injury-, or misfolded protein-induced degeneration in Drosophila and in mammalian neurons. Here, we show that NMNAT is also a novel stress response protein required for thermotolerance and mitigation of oxidative stress-induced shortened lifespan. NMNAT is transcriptionally regulated during various stress conditions including heat shock and hypoxia through heat shock factor (HSF) and hypoxia-inducible factor 1␣ in vivo. HSF binds to nmnat promoter and induces NMNAT expression under heat shock. In contrast, under hypoxia, HIF1␣ up-regulates NMNAT indirectly through the induction of HSF. Our studies provide an in vivo mechanism for transcriptional regulation of NMNAT under stress and establish an essential role for this neuroprotective factor in cellular stress response.When faced with abnormal conditions, such as heat, oxidative stress, hypoxia, or accumulation of aberrant proteins, cells implement a stress response program to protect themselves and ensure survival. Stress conditions can cause protein unfolding, misfolding, or aggregation, and the consequent inadequate response to stress can lead to developmental defects, shortened lifespan, and neurodegenerative conditions (for review, see Ref.2). The increased synthesis of molecular chaperone heat shock proteins (HSPs) 2 is central to the stress response because they function to prevent protein misfolding and aggregation to maintain protein homeostasis (1, 2). It is thought that elevated expression of HSPs is sufficient to protect cells from a wide range of cytotoxic conditions (1, 3, 4). However, it is unclear whether the stress response network includes essential genes other than HSPs. Although a few metabolic enzymes have been found to be up-regulated upon stress (5, 6), it is unclear whether metabolic enzymes are an integral part of the stress response network.Heat shock factors (HSFs) are the master stress transcription factors of heat shock response, with one HSF in invertebrates and multiple HSFs in plants and vertebrates (7-9). Through their roles in mediating transcriptional activation of HSP genes, HSFs function in maintaining protein homeostasis and integrating cellular response to stress and development (10). Upregulation of HSPs by HSF1 is triggered by a variety of acute and chronic stress conditions and disease states (11). When faced with other stress conditio...

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“…For example, Nmnat2 is predominantly expressed in brain and weakly expressed in heart and skeletal muscle Raffaelli et al, 2002;Berger et al, 2005). Specifically, Nmnat2 is highly expressed in cerebral cortex and detectable in midbrain, cerebellum, olfactory bulb, striatum and hippocampus (Yan et al, 2009). On the other hand, mitochondrial Nmnat3 is strongly expressed in kidney, lung and spleen, where Nmnat2 expression is low (Lau et al, 2009).…”

Section: Nmnats and Axon Degenerationmentioning

confidence: 99%

“…Our recent research revealed that Nmnat2 mRNA level was remarkably decreased in hippocampus of aged APPswe/ PS1dE9 transgenic mice (Yan et al, 2009), a model for Alzheimer's disease (Morrissette et al, 2009). Over-expression of human Nmnat2 was reported to protect the axons from degeneration in transected cultured SCGs (Yan et al, 2009), while over-expression of mouse Nmnat2 failed to suppress axon degeneration in transected Drosophila ORN (Avery et al, 2009).…”

Section: Nmnats and Axon Degenerationmentioning

confidence: 99%

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WldS, Nmnats and axon degeneration-progress in the past two decades

Yan

et al. 2010

Protein Cell

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A chimeric protein called Wallerian degeneration slow (Wld S ) was first discovered in a spontaneous mutant strain of mice that exhibited delayed Wallerian degeneration. This provides a useful tool in elucidating the mechanisms of axon degeneration. Over-expression of Wld S attenuates the axon degeneration that is associated with several neurodegenerative disease models, suggesting a new logic for developing a potential protective strategy. At molecular level, although Wld S is a fusion protein, the nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) is required and sufficient for the protective effects of Wld S , indicating a critical role of NAD biosynthesis and perhaps energy metabolism in axon degeneration. These findings challenge the proposed model in which axon degeneration is operated by an active programmed process and thus may have important implication in understanding the mechanisms of neurodegeneration. In this review, we will summarize these recent findings and discuss their relevance to the mechanisms of axon degeneration.

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Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity

Cited by 83 publications

References 36 publications

Rescue of Peripheral and CNS Axon Defects in Mice Lacking NMNAT2

Rescue of Peripheral and CNS Axon Defects in Mice Lacking NMNAT2

Nicotinamide Mononucleotide Adenylyltransferase Is a Stress Response Protein Regulated by the Heat Shock Factor/Hypoxia-inducible Factor 1α Pathway

WldS, Nmnats and axon degeneration-progress in the past two decades

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