Verghese PB, Sasaki Y, Yang D, Stewart F, Sabar F, Finn MB, Wroge CM, Mennerick S, Neil JJ, Milbrandt J, Holtzman DM. Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):19054-9. PubMed.
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Johns Hopkins University School of Medicine
This new study by Verghese et al. is a huge step in the right direction concerning mechanisms of neurodegeneration in neonatal hypoxia-induced encephalopathy (HIE). The field has been side-tracked, maybe even lost, for quite some time with the resurrection of apoptosis in the developing nervous system and its possible role in brain injury. It seems to have been forgotten that the overwhelming majority of the neurodegeneration seen in neonatal human HIE and in animal model HIE has more of a necrotic phenotype (see Northington et al., 2011; Martin, 2001). The work by Verghese et al. on Nmnat1 is consistent with this idea. A problem, though, with neonatal mouse models of HIE is the troublesome inherent variability in the damage, even among gender-matched littermates, and the robust strain effects, especially in investigations of cerebral ischemia and excitotoxicity. It will be extraordinarily important to get this work translated to large animal models of neonatal HIE to fully determine its relevance as a mechanism of brain injury.
References:
Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol. 2011 May;69(5):743-58. PubMed.
Martin LJ. Neuronal cell death in nervous system development, disease, and injury (Review). Int J Mol Med. 2001 May;7(5):455-78. PubMed.
View all comments by Lee J. MartinBabraham Institute
The paper makes some interesting findings, but also raises some questions. Figures 1 and 2 are particularly impressive, showing major protection from tissue loss in the cytNmnat1 neonates. This result is limited to magnetic resonance imaging and low-resolution sections, so it would be useful to know what is happening at the cellular level, in particular, whether cell death is actually prevented in vivo.
The reduced NAD loss is also intriguing. Interestingly, there was an earlier suggestion that synthesis of NAD was not the reason why cytNmnat1 projects injured axons (Sasaki et al., 2009). I wonder whether there are other changes happening, and whether any are more causatively connected with tissue damage.
There is a striking reduction in lactate dehydrogenase release as an indirect measure of cell death. It would be nice to see the protected cell bodies and a direct quantification of their numbers, or propidium iodide staining, for example. Cell survival in vivo seems not to be assessed (unless I missed something in the supplementary figures), but if it occurs, it could still be secondary to axon survival. A similar finding is likely to underlie the preservation of both motor axons and cell bodies in progressive motor neuronopathy mice by Wlds (Ferri et al., 2003).
A study of Wlds in transient ischemia in adults also found protection of cell bodies (Gillingwater et al, 2004). From the point of view of Alzheimer's disease, this could be important because adult nervous systems should better model a disorder of the aging brain. Nevertheless, as the authors point out, hypoxia-ischemia is also very important in newborns.
I am intrigued by the fact that cytNmnat1 tissues show a huge increase in caspase-3 activity but still survive (Fig 4). I think this actually raises the question of whether cytNmnat1 is blocking a step downstream of caspase-3. It's hard to imagine that this increase in caspase-3 activity makes no contribution to cell death.
Regarding the implications for various neurodegenerative disorders, a lot depends on the pathogenic mechanisms in each disease. If ischemia is involved, which, in AD could be the case, this, together with the study in adult animals mentioned above, could be a useful step forward.
In summary, there is clearly strong protection from ischemic damage by an Nmnat enzyme, which in neonates at least is the first example. CtyNmnat1 may well be working downstream of NMDA excitotoxicity, but it will be important to learn more about the cell survival, including a direct demonstration and its causative relationship to axon survival.
References:
Sasaki Y, Vohra BP, Lund FE, Milbrandt J. Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide. J Neurosci. 2009 Apr 29;29(17):5525-35. PubMed.
Ferri A, Sanes JR, Coleman MP, Cunningham JM, Kato AC. Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr Biol. 2003 Apr 15;13(8):669-73. PubMed.
Gillingwater TH, Haley JE, Ribchester RR, Horsburgh K. Neuroprotection after transient global cerebral ischemia in Wld(s) mutant mice. J Cereb Blood Flow Metab. 2004 Jan;24(1):62-6. PubMed.
View all comments by Michael ColemanEmory University School of Medicine
An interesting paper extending the literature on axonal and neuronal protection by Nmnat1 to another model of neurological injury. An intriguing aspect of this study is that Nmnat1 protects against hypoxic-ischemia injury, but does not seem to affect the activation of caspase-3 or standard apoptosis pathways. This finding further emphasizes the fact that neuronal and axonal death may proceed by independent pathways, and identification of the relevant pathways will be important for designing and developing new therapeutics.
View all comments by Jonathan D. GlassMake a Comment
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