An alternative, nonapoptotic form of programmed cell death

Sperandio, Sabina; Belle, Ian de; Bredesen, Dale E.

doi:10.1073/pnas.97.26.14376

Cited by 860 publications

(834 citation statements)

References 42 publications

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“…Although initially disputed, several forms of caspase-independent apoptosis [33][34][35] or forms that are similar to apoptosis ('paraptosis') but also do not involve caspases have been reported. 30,36 Sperandio and colleagues (2000) characterized 'paraptosis' in 293T cells and mouse embryonic fibroblasts as a form of cell death without nuclear fragmentation and apoptotic bodies, but with cytoplasmic vacuolation and late mitochondrial swelling. In addition, death was independent of caspase activity, Bcl-X L , and was executed without DNA fragmentation.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that neuronal death induced by either potassium deprivation or blocking the NHE is mediated by different cell death pathways. Sperandio et al (2000) 30 recently introduced the concept of 'paraptosis', an alternative, nonapoptotic form of programmed cell death, that did not show a response to caspase inhibitors and Bcl-X L , but to cycloheximide. Treatment with cycloheximide blocked the death of cerebellar granule neurons after potassium withdrawal and after treatment with HOE 642 (Figure 7a).…”

Section: Death Of Cerebellar Granule Neurons Induced By Hoe 642 or Eimentioning

confidence: 99%

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Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

et al. 2004

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Potassium withdrawal is commonly used to induce caspasemediated apoptosis in cerebellar granule neurons in vitro. However, the underlying and cell death-initiating mechanisms are unknown. We firstly investigated potassium efflux through the outward delayed rectifier K þ current (I k ) as a potential mediator. However, tetraethylammoniumchloride, an inhibitor of I k , was ineffective to block apoptosis after potassium withdrawal. Since potassium withdrawal reduced intracellular pH (pH i ) from 7.4 to 7.2, we secondly investigated the effects of intracellular acidosis. To study intracellular acidosis in cerebellar granule neurons, we inhibited the Na þ /H þ exchanger (NHE) with 4-isopropyl-3-methylsulfonylbenzoylguanidine methanesulfonate (HOE 642) and 5-(N-ethyl-Nisopropyl)-amiloride. Both inhibitors concentration-dependently induced cell death and potentiated cell death after potassium withdrawal. Although inhibition of the NHE induced cell death with morphological criteria of apoptosis in light and electron microscopy including chromatin condensation, positive TUNEL staining and cell shrinkage, no internucleosomal DNA cleavage or activation of caspases was detected. In contrast to potassium withdrawal-induced apoptosis, cell death induced by intracellular acidification was not prevented by insulin-like growth factor-1, cyclo-adenosinemonophosphate, caspase inhibitors and transfection with an adenovirus expressing Bcl-X L . However, cycloheximide protected cerebellar granule neurons from death induced by potassium withdrawal as well as from death after treatment with HOE 642. Therefore, the molecular mechanisms leading to cell death after acidification appear to be different from the mechanisms after potassium withdrawal and resemble the biochemical but not the morphological characteristics of paraptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Death Of Cerebellar Granule Neurons Induced By Hoe 642 or Eimentioning

confidence: 99%

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

et al. 2004

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“…It has been suggested that, when caspases are inhibited, other factors, released from mitochondria in a caspase-independent manner, can trigger a secondary nonapoptotic form of death. 17 Apoptosis-inducing factor (AIF 18 ) has been related to a nonapoptotic morphotype in several cell types and conditions, for example, Apaf1 À/À interdigital web cells 19 and primary hippocampal neurons. 20 More recently, the independence of AIF release from caspase activation has been questioned.…”

Section: Etna Cells Apoptosis Induced By Neurodegenerative Stimuli Ismentioning

confidence: 99%

Apoptosome inactivation rescues proneural and neural cells from neurodegeneration

et al. 2004

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Deficiency of the apoptosome component Apaf1 leads to accumulation of supernumerary brain cells in mouse embryos. We observed that neural precursor cells (NPCs) in Apaf1 À/À embryos escape programmed cell death, proliferate and retain their potential to differentiate. To evaluate the circumstances of Apaf1 À/À NPC survival and investigate their fate under neurodegenerative conditions, we established cell lines of embryonic origin (ETNA). We found that Apaf1 À/À NPCs resist common apoptotic stimuli and neurodegenerative inducers such as amyloid-b peptide (typical of Alzheimer's disease) and mutant G93A superoxide dismutase 1 (typical of familial amyotrophic lateral sclerosis). Similar results were obtained in Apaf1 À/À primary cells. When death is prevented by Apaf1 deficiency, cytochrome c is released from mitochondria and rapidly degraded by the proteasome, but mitochondria remain intact. Under these conditions, neither activation by cleavage of initiator caspases nor release of alternative apoptotic inducers from mitochondria takes place. In addition, NPCs can still differentiate, as revealed by neurite outgrowth and expression of differentiation markers. Our findings imply that the mitochondrion/apoptosome pathway is the main route of proneural and neural cells to death and that its inhibition prevents them from dismantling in neurodegenerative conditions. Indeed, the ETNA cell model is ideally suited for exploring the potential of novel cell therapies for the treatment of human neurodegenerations.

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“…Although pcd has often been equated with apoptosis, it has become increasingly clear that nonapoptotic forms of pcd also exist. [1][2][3][4][5][6][7][8][9][10][11][12][13] For example, certain developmental cell deaths, such as 'autophagic' cell death [1][2][3][4][5] and 'cytoplasmic' cell death, 2,4,6-9 do not resemble apoptosis. Furthermore, neurodegenerative diseases such as Huntington's disease and amyotrophic lateral sclerosis demonstrate neuronal cell death that does not fulfill the criteria for apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix

et al. 2004

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Programmed cell death (pcd) may take the form of apoptotic or nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here, we report that paraptosis, an alternative, nonapoptotic cell death program that may be induced by the insulin-like growth factor I receptor (among other inducers), is mediated by mitogen-activated protein kinases (MAPKs) and inhibited by AIP-1/Alix. The inhibition by AIP-1/Alix is specific for paraptosis since apoptosis was not inhibited. Caspases were not activated in this paradigm, nor were caspase inhibitors effective in blocking cell death. However, insulinlike growth factor I receptor (IGFIR)-induced paraptosis was inhibited by MEK-2-specific inhibitors and by antisense oligonucleotides directed against c-jun N-terminal kinase-1 (JNK-1). These results suggest that IGFIR-induced paraptosis is mediated by MAPKs, and inhibited by AIP-1/Alix.

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An alternative, nonapoptotic form of programmed cell death

Cited by 860 publications

References 42 publications

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Apoptosome inactivation rescues proneural and neural cells from neurodegeneration

Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix

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