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10.4 Gene Transcription and DNA Damage
A very useful model for DNA damage in the brain is the tertiary-butylhy- droperoxide (tBuOOH) model.84,85 Following intracerebroventricular injection of tBuOOH, DNA fragments within minutes followed by apoptosis and necrosis of many cells in the brain.70 DNA fragmentation and PARP activation lead to changes in gene expression within 1 hour or more (Table 10.1).86 Most of the genes are involved in apoptosis. Reactive oxygen species, such as hydrogen peroxide, at the cell surface activate TNFR that activates caspases 3, 6, 7 and 8. Hydrogen peroxide penetrates into the cell and inactivates various cytoplasmic IAPs. Hydrogen peroxide also penetrates into the nucleus, fragments DNA, activates PARP and increases the transcription of genes for caspases 3, 6 and 7. Hydrogen peroxide penetrates into the endoplasmic reticulum and increases the release of active caspase 4. All of these events are critical to the induction of apoptosis. Of course, apoptosis is a cascade of several events for which the full sequence is not completely understood. However, if enough pro-apoptotic events are activated and enough antiapoptotic events are inhibited, apoptosis occurs. Nicotinamide can prevent apoptosis by interfering with the cascade of apoptotic events.86
As mentioned above, PARP and p53 bind to DNA breaks and become activated. Another protein that is activated and involved in altering gene transcription during DNA damage is cohesin.87 Cohesin is required to hold together the chromatid pairs. There is a variety of p53-mediated alterations in gene expression following DNA damage. These alterations involve activation of the forkhead transcription factor (Foxp3).88 DNA damage leads to histone activation and neovascularization, that may be critical in stroke.89 Neovascularization helps restore blood flow to brain areas that are recovering from stroke. It is not clear if neovascularization is helpful or harmful in Alzheimer’s
Table 10.1 List of genes observed to be significantly di erently expressed between t-BuOOH treated and control HCN2 cells 1 to 6 hrs following analysis.
Name of gene |
Gene ID |
|
|
Bcl2 like 11 |
NM_006538 |
TNF (ligand) superfamily, member 9 |
NM_003811 |
Caspase 4 |
NM_001225 |
Nucleolar protein 3 |
NM_003946 |
Lymphotoxin beta receptor (TNFR superfamily, member 3) |
NM_002342 |
Myeloid cell leukemia sequence (mcl-1) |
NM_021960 |
Bacculoviral IAP containing repeat 6 |
NM_016252 |
cIAP1 |
NM_001166 |
cIAP2 |
NM_001165 |
Mdm-2 |
NM_002392 |
TNFR2 |
NM_001066 |
|
|
Bcl2 like 11 is the B-cell lymphoma 2 like 11 gene also called apoptosis facilitator. TNFR is tumor necrosis factor receptor. IAP is inhibitor of apoptosis proteins. Mdm is murine double minute oncogene, a suppressor of P53 expression.
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disease and Parkinson’s disease. Neovascularization can produce arterioles that leak until they become well established and form tight junctions between endothelial cells. Leaky arterioles may produce more damage in stroke, Alzheimer’s disease and Parkinson’s disease.
10.5 Conclusions
Neurodegeneration may be caused by or increased by toxic lifestyles. Diet and exercise improvements could be encouraged to prevent or perhaps control neurodegenerative diseases. Toxic lifestyles lead to adipokine elevations in the blood and oxygen radical formation, possibly through visfatin, CD38 and NADH oxidase mechanisms. Hydrogen peroxide formed during this process crosses cell membranes and damages DNA. The cells first damaged in this process are probably the endothelial cells of the blood-brain barrier. Adipokines cause white blood cells and platelets to stick to the damaged blood-brain barrier. This sets up an inflammatory process that produces more damage. The leaky blood-brain barrier allows the infiltration of inflammatory cells into the brain parenchyma. These inflammatory cells produce oxygen radicals that damage the DNA in neurons and other brain cells leading to brain lesions. In Alzheimer’s disease these lesions are most important in the hippocampus, cerebral cortex and other areas. In Parkinson’s disease these lesions are critical in the dopaminergic neurons of the substantia nigra, dopaminergic neuronal projections in the basal ganglia and other regions.
Stroke is a rapid process that also involves toxic lifestyles. Adipokines damage arteries in the body. Clots and thrombi are produced that lodge in the middle cerebral artery and other locations to produce ischemia, followed later by reperfusion as the clot or thrombus is removed or resolves. Ischemia and reperfusion produce oxygen radicals and hydrogen peroxide that damage cellular DNA leading to cell death through apoptosis and necrosis. Brain lesions are typically seen in the basal ganglia, hippocampus, cerebral cortex and other regions.
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