Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS.
Regional analysis of p53 mutations in rheumatoid arthritis synovium.
Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10025-30.
PubMed.
The problem of p53 mutations leading to clonal expansion and hence exacerbation of inflammation is pertinent only to cells that divide. In other words the expansion and resulting increase, in this case of the inflammatory response, can only take place because certain cells (in the synovium in this case) divide and hence generate a colony of cells with altered p53, which has detrimental consequences. In contrast, a somatic mutation in the p53 gene in a neuron would not have the same detrimental effect because this mutation would not be passed on to any additional neurons through division. I therefore feel that this mechanism may not be valid for postmitotic neurons. On the other hand, the brain is mysterious, and there is much we do not know about how neurons function. It is also possible that, were such p53 mutations to occur in glial cells of the brain, cells that are capable of division, the toxic by-products released by the newly formed defective glia could have an impact on the health of neighboring neurons.
Overall, I think it may be a bit of a stretch to imply any relevance of this paper to neurodegeneration. This is a more conservative view, but I have tried to stress caution in the field, especially because several people do confuse the neurogenesis of stem cells in brain with the cell cycle phenomena occurring in the fully mature, non-dividing neurons of Alzheimer’s disease brain.
Comments
The problem of p53 mutations leading to clonal expansion and hence exacerbation of inflammation is pertinent only to cells that divide. In other words the expansion and resulting increase, in this case of the inflammatory response, can only take place because certain cells (in the synovium in this case) divide and hence generate a colony of cells with altered p53, which has detrimental consequences. In contrast, a somatic mutation in the p53 gene in a neuron would not have the same detrimental effect because this mutation would not be passed on to any additional neurons through division. I therefore feel that this mechanism may not be valid for postmitotic neurons. On the other hand, the brain is mysterious, and there is much we do not know about how neurons function. It is also possible that, were such p53 mutations to occur in glial cells of the brain, cells that are capable of division, the toxic by-products released by the newly formed defective glia could have an impact on the health of neighboring neurons.
Overall, I think it may be a bit of a stretch to imply any relevance of this paper to neurodegeneration. This is a more conservative view, but I have tried to stress caution in the field, especially because several people do confuse the neurogenesis of stem cells in brain with the cell cycle phenomena occurring in the fully mature, non-dividing neurons of Alzheimer’s disease brain.
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