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Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+.

ABSTRACT: Trophic deprivation-mediated neuronal death is important during development, after acute brain or nerve trauma, and in neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro, and an in vivo model is provided by neuronal death in the mouse dorsal lateral geniculate nucleus (LGNd) after ablation of the visual cortex (VCA). Oxidant-induced intracellular Zn(2+) release ([Zn(2+) ](i) ) from metallothionein-3 (MT-III), mitochondria or 'protein Zn(2+) ', was implicated in trophic deprivation neurotoxicity. We have previously shown that neurotoxicity of extracellular Zn(2+) required entry, increased [Zn(2+) ](i) , and reduction of NAD(+) and ATP levels causing inhibition of glycolysis and cellular metabolism. Exogenous NAD(+) and sirtuin inhibition attenuated Zn(2+) neurotoxicity. Here we show that: (1) Zn(2+) is released intracellularly after oxidant and SD injuries, and that sensitivity to these injuries is proportional to neuronal Zn(2+) content; (2) NAD(+) loss is involved - restoration of NAD(+) using exogenous NAD(+) , pyruvate or nicotinamide attenuated these injuries, and potentiation of NAD(+) loss potentiated injury; (3) neurons from genetically modified mouse strains which reduce intracellular Zn(2+) content (MT-III knockout), reduce NAD(+) catabolism (PARP-1 knockout) or increase expression of an NAD(+) synthetic enzyme (Wld(s) ) each had attenuated SD and oxidant neurotoxicities; (4) sirtuin inhibitors attenuated and sirtuin activators potentiated these neurotoxicities; (5) visual cortex ablation (VCA) induces Zn(2+) staining and death only in ipsilateral LGNd neurons, and a 1 mg/kg Zn(2+) diet attenuated injury; and finally (6) NAD(+) synthesis and levels are involved given that LGNd neuronal death after VCA was dramatically reduced in Wld(s) animals, and by intraperitoneal pyruvate or nicotinamide. Zn(2+) toxicity is involved in serum and trophic deprivation-induced neuronal death.

SUBMITTER: Sheline CT

PROVIDER: S-EPMC2946389 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFerroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.MethodsTo elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.ResultsWe found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective.ConclusionsBy showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.

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Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+.

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