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Biochemical and Temporal Analysis of Events Associated with Apoptosis Induced by Lowering the Extracellular Potassium Concentration in Mouse Cerebellar Granule Neurons (1997)

Nardi, Nurit ; Avidan, Galya ; Daily, Dvorah ; [et al.]

Oxford, UK : Blackwell Science Ltd

Journal of neurochemistry 68 (1997), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: We analyzed biochemically and temporally the molecular events that occur in the programmed cell death of mouse cerebellar granule neurons deprived of high potassium levels. An hour after switching the neurons to a low extracellular K+ concentration ([K+]o), a significant part of the genomic DNA was already cleaved to high-molecular-weight fragments. This phenomenon was intensified with the progression of the death process. Addition of cycloheximide to the neurons 4 h after high [K+]o deprivation resulted in no cell loss and complete recovery of the damaged DNA. DNA margination and nuclear fragmentation as assessed by 4,6-diaminodiphenyl-2-phenylindole staining were observable in a few cells beginning ∼4 h after the removal of high [K+]o and developed to nuclear condensation 4 h later. Six hours after high [K+]o deprivation, the DNA was fragmented into oligonucleosome-sized fragments. Within 6 h after removal of the extracellular K+, 50% of the neurons were committed to die and lost their ability to be rescued by readministration of 25 mM [K+]o. Similar to high [K+]o deprivation, inhibition of RNA or protein synthesis failed to halt neuronal degeneration of a similar percentage of cells 6 h after the onset of the death process. Mitochondrial function steadily decreased after [K+]o removal. An ∼40% decrease in RNA and protein synthesis was detected by 6 h of [K+]o removal during the period of cell death commitment; rates continued to decline gradually thereafter. The temporal characteristics of the DNA damage and recovery, DNA cleavage to oligonucleosome-sized fragments, and the reduction in mitochondrial activity—events that occurred within the critical time—may indicate that these processes have an important part in the mechanism that committed the neurons to die.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68020750.x

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The Involvement of p53 in Dopamine-Induced Apoptosis of Cerebellar Granule Neurons and Leukemic Cells Overexpressing p53 (1999)

Daily, Dvorah ; Barzilai, Ari ; Offen, Daniel ; [et al.]

Springer

Cellular and molecular neurobiology 19 (1999), S. 261-276

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ISSN: 1573-6830

Keywords: Parkinson's disease ; catecholamines ; oxidative metabolites ; phosphorylation ; DNA damage ; apoptosis ; p53

Source: Springer Online Journal Archives 1860-2000

Topics: Biology

Notes: Abstract 1. The pathogenesis of the selective degeneration of the dopaminergic neurons in Parkinson's disease is still enigmatic. Recently we have shown that dopamine can induce apoptosis in postmitotic neuronal cells, as well as in other cellular systems, thus suggesting a role for this endogenous neurotransmitter and associated oxidative stress in the neuronal death process. 2. Dopamine has been shown to be capable of inducing DNA damage through its oxidative metabolites. p53 is a transcription factor that has a major role in determining cell fate in response to DNA damage. We therefore examined the possible correlation between dopamine-triggered apoptosis, DNA damage and levels of total phosphorylated p53 protein in cultured mouse cerebellar granule neurons. 3. Marked DNA damage and apoptotic nuclear condensation and fragmentation were detected within several hours of exposure to dopamine. An associated marked threefold increase in p53 phosphorylation was observed within this time window. Using a temperature-sensitive p53 activation system in leukemia LTR6 cells, were found that p53 inactivation dramatically attenuated dopamine toxicity. 4. We therefore conclude that DNA damage and p53 activation may have a role in mediating dopamine-induced apoptosis. Modulation of the p53 system may therefore have a protective role against the toxicity of this endogenous neurotransmitter and associated oxidative stress.