The following has been cut and pasted from other threads but may show convergant processes in ALS concerning VEGF, ANG by upregulating Bcl-2, which inhibits caspase-3.
Vascular endothelial cell growth factor (VEGF) requires ANG rRNA transcription to function correctly to protect neurons. Bcl-2 and Nf-κb pathways are also involved, so are all these pathways common to most ALS cases?
Molecular biology of amyotrophic lateral sclerosis: insights from genetics
Complex genetics in ALS.
There have been few studies of genetic variants that modify ALS susceptibility or phenotype.
In DNA sets from Sweden, Belgium and Birmingham (UK)44, but not London (UK)44, Utrecht (The Netherlands)45 or Boston (USA) (R.H.B.,unpublished data), promoter polymorphisms that reduce the expression of vascular endothelial growth factor (VEGF) are associated with an increased risk of disease.
Variants predicted to reduce the activity of another vascularizing factor, angiogenin (ANG), increase ALS risk selectively in Irish and Scottish DNA sets46.
These observations support the view that vascularization and, indirectly, blood supply and cellular oxygen pressure are important determinants of motor neuron viability,
or that VEGF and ANG exert direct neurotrophic influences on motor neurons.
http://www.researchals.org/uploaded_files/pasinelli_nns_rev_0906_844ub6.pdfANG moves to the nuclear in endothelial cells where it binds a to a region of rDNA which then stimulates rRNA transcription. Vascular endothelial cell growth factor (VEGF) requires ANG rRNA transcription to function correctly to protect neurons. VEGF protects motor neurons from ischemic injury, death and if disrupted motor neurons degenerate.
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Angiogenin is found in a variety of cells throughout the body and circulates in the bloodstream. When angiogenin binds to receptors on the surface of endothelial cells, it triggers a series of reactions that brings angiogenin inside the cell.
Once inside endothelial cells, angiogenin moves to the nucleus where it stimulates the production of ribosomal RNA (rRNA), a chemical cousin of DNA. Ribosomal RNA is required for assembling protein building blocks (amino acids) into functioning proteins.
Angiogenin stimulates the production of additional ribosomal RNA when there is an increased demand for proteins, such as for the growth and division of endothelial cells. Angiogenin may also be involved in other steps of angiogenesis, such as helping to break down the tissue that surrounds existing blood vessels to allow room for the growth of new blood vessels
Angiogenin is a liver-derived component of normal serum the concentration of which can increase in various disease states and its expression is regulated in vivo in a manner that is characteristic of acute phase proteins (Olson et al, 1998).
In the current work, Li and Hu lay out the biochemical pathway linking angiogenin and apoptosis inducing factor (AIF). AIF is normally located in mitochondria, but when it moves to the nucleus—as it does in ALS model mice (Oh et al., 2006)—it chews up DNA, contributing to apoptosis.
The following indicates that angiogenin stops AIF moving to the nucleus by up regulating Bcl-2 which inhibits caspase-3 ......Therefore giving an explanation of the death or destructive pathway.
Critically is this common in most ALS cases albeit by slightly different but related pathways and the cause of neuron death?
(In addition to angiogenin and AIF, the players include the apoptosis dampener Bcl-2 and the pro-apoptosis proteins caspase-3 and serum polymerase-1 (PARP-1).
The researchers delineate a pathway in which apoptosis normally proceeds from activation of caspase-3, to cleavage of PARP-1, to nuclear translocation of AIF.
Angiogenin alters the situation by upregulating Bcl-2, which inhibits caspase-3 and thus the rest of the downstream pathway. Much of this pathway was already known, noted Piera Pasinelli of Thomas Jefferson University in Philadelphia, Pennsylvania, but “they really teased out the mechanism by which angiogenin can be anti-apoptotic…in a Bcl-2-dependent manner,” she said.
To study apoptosis, the researchers starved P19 cells of serum. This treatment normally causes PARP-1 cleavage within a few hours and nuclear translocation of AIF by 24. But with angiogenin in the culture media, PARP-1 stayed whole and AIF remained mitochondrial, confirming that angiogenin blocks apoptosis via this pathway. In a previous study, the authors confirmed that angiogenin also prevents activation of caspase-3 (Li et al., 2010).
The researchers already knew Bcl-2 was upregulated by angiogenin (Li et al., 2010), and suspected it would be crucial to angiogenin’s effects. If so, then removing Bcl-2 should allow apoptosis to proceed unhindered, even in the presence of angiogenin. Li used RNA interference to knock down Bcl-2. In the knocked down, serum-starved cell cultures, angiogenin was less effective at preventing caspase-3 activation, PARP-1 cleavage and AIF translocation.)
Notice in the above the researchers said, in the last paragraph, that angiogenin was less effective which implies that it did not totally stop caspase-3 activation so is there another factor at work?
Angiogenin upregulates anti-apoptotic genes, including Bag1, Bcl-2, Hells, Nf-κb and Ripk1, and downregulates pro-apoptotic genes, such as Bak1, Tnf, Tnfr, Traf1 and Trp63.
Knockdown of Bcl-2 largely abolishes the anti-apoptotic activity of angiogenin, whereas the inhibition of Nf-κb activity results in a partial, but significant, inhibition of the protective activity of angiogenin.
Thus, angiogenin prevents stress-induced cell death through both the Bcl-2 and Nf-κb pathways.
From the above it looks like upregulating Bcl-2 and Nf-kb through some other method may also help us besides increasing angiogenin levels?
Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again