Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

Niquet, Jérôme; Baldwin, Roger A.; Allen, Sorcha; Fujikawa, Denson G.; Wasterlain, Claude G.

doi:10.1073/pnas.0530113100

Cited by 79 publications

(75 citation statements)

References 35 publications

(23 reference statements)

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“…Antibodies were tagged with either Alexa Fluor 594 (donkey anti-rabbit for CC3, 1:400) or 488 (donkey anti-mouse for TH, orex, or HDC, 1:1000; Invitrogen). Wake neurons with visible nuclei were examined not only for nuclear CC3 but also for cytoplasmic CC3, as observed in hypoxic programmed necrosis in dopaminergic neurons (Niquet et al, 2003). Cytoplasmic and nuclear CC3 presence was determined separately using Image-Pro Plus software (Media Cybernetics, Silver Spring, MD) to measure fluorescence intensity relative to background (adjacent non-TH region).…”

Section: Methodsmentioning

confidence: 99%

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Zhu¹,

Fenik²,

Zhan³

et al. 2007

J. Neurosci.

165

117

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The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/ reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/ reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67 phox to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.

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Section: Methodsmentioning

confidence: 99%

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Zhu¹,

Fenik²,

Zhan³

et al. 2007

J. Neurosci.

165

117

View full text Add to dashboard Cite

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“…Rapid death with a necrotic morphology can result from direct release of cytochrome c from calcium-overloaded, energy-depleted mitochondria, followed by activation of caspase-9 and -3. Such "programmed necrosis" is seen after hypoxic/ischemic neuronal necrosis in primary cultures of dentate gyrus (12). It may also contribute to neuronal death from SE in the adult brain (13), which is characterized by a predominantly necrotic morphology (14) and by calcium overload of neuronal mitochondria (15; Figure 1).…”

Section: Figurementioning

confidence: 99%

Bim, Bad, and Bax: a deadly combination in epileptic seizures

Niquet¹,

Wasterlain²

2004

J. Clin. Invest.

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Several Bcl-2 family members, including Bim, may contribute to programmed cell death by inducing mitochondrial cytochrome c release, which activates caspase-9 and then caspase-3, the “executioner” of the cell. In this issue of the JCI, Shinoda and collaborators show the key role of Bim in epileptic seizure–induced neuronal injury and identify the contribution of transcription factors responsible for seizure-induced Bim upregulation

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“…For apoptosis, the nucleus usually undergoes condensation, chromatin marginalization and fragmentation into a few large and regular chromatin clumps, which are eventually packed into apoptotic bodies (Kerr et al, 1972;Niquet et al, 2003). In contrast, nuclei in necrotic cells condense into to smaller chromatin clumps with irregular and dispersed morphologies, which might be dissolved later (Bortul et al, 2001;Fujikawa et al, 2000;Hardingham et al, 2002;Niquet et al, 2003). Therefore, based on the morphology of nuclear fragmentation, pyknosis can be divided into nucleolytic pyknosis (mainly occurring in apoptosis) and anucleolytic pyknosis (mainly occurring in necrosis) (Burgoyne, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, based on the morphology of nuclear fragmentation, pyknosis can be divided into nucleolytic pyknosis (mainly occurring in apoptosis) and anucleolytic pyknosis (mainly occurring in necrosis) (Burgoyne, 1999). Although pyknosis has been widely considered as a marker of cell death in vitro and in vivo (Colbourne et al, 1999;Fujikawa et al, 1999Fujikawa et al, , 2010Ji et al, 2013;Niquet et al, 2003;Sohn et al, 1998), it is unclear whether pyknosis is a regulated process.…”

Section: Introductionmentioning

confidence: 99%

Necrotic pyknosis is a morphologically and biochemically distinct event from apoptotic pyknosis

Hou

et al. 2016

Journal of Cell Science

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Classification of apoptosis and necrosis by morphological differences has been widely used for decades. However, this usefulness of this method has been seriously questioned in recent years, mainly due to a lack of functional and biochemical evidence to interpret the morphology changes. To address this matter, we devised genetic manipulations in Drosophila to study pyknosis, a process of nuclear shrinkage and chromatin condensation that occurs in apoptosis and necrosis. By following the progression of necrotic pyknosis, we surprisingly observed a transient state of chromatin detachment from the nuclear envelope, followed by the nuclear envelope completely collapsing onto chromatin. This phenomenon led us to discover that phosphorylation of barrier-to-autointegration factor (BAF) mediates this initial separation of nuclear envelope from chromatin. Functionally, inhibition of BAF phosphorylation suppressed necrosis in both Drosophila and human cells, suggesting that necrotic pyknosis is conserved in the propagation of necrosis. In contrast, during apoptotic pyknosis the chromatin did not detach from the nuclear envelope and inhibition of BAF phosphorylation had no effect on apoptotic pyknosis and apoptosis. Our research provides the first genetic evidence supporting a morphological classification of apoptosis and necrosis through different forms of pyknosis.

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Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

Cited by 79 publications

References 35 publications

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Bim, Bad, and Bax: a deadly combination in epileptic seizures

Necrotic pyknosis is a morphologically and biochemically distinct event from apoptotic pyknosis

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