Oxidative stress and inflammation are thought to play significant roles in the pathology of many disorders, including neurodegenerative diseases such as Alzheimer’s and amyotrophic lateral sclerosis (ALS). Could the protein p53, named molecule of the year by Science magazine in 1993 but best known for its tumor suppressor activity, initiate these processes? The idea may seem a little far-fetched, but work published in July 23 PNAS suggests this may be exactly what happens-at least in the case of rheumatoid arthritis (RA).

Researchers at Gary Firestein’s lab, University of California at San Diego, together with colleagues from the La Jolla Institute of Allergy and Immunology, analyzed p53 mutations in somatic cells from the synovial tissue of arthritis sufferers. They found clusters of non-cancerous p53 mutations in the synovial intimal lining, suggesting that cells harboring these mutations had undergone many rounds of division. Significantly, the authors found that these regions of clonal expansion were associated with higher levels of the pro-inflammatory cytokine interleukin-6 (IL-6), a downstream target of p53. In addition, most of the mutations found were of the transitional type, which can arise by oxidative damage to DNA.

The data suggests that oxidative DNA damage of the p53 gene may set off an inflammatory cascade that contributes to RA. But could this be true for other diseases? “Since an inflammatory component is well established in AD, the possibility that p53 mutations are associated with this inflammatory response is of interest,” said Paul Coleman, University of Rochester Medical Center, New York, who has advanced microdissection techniques that may be useful in answering this question. The Firestein group did try laser capture microdissection, a method capable of separating cells from complex tissues, but could not collect sufficient material for analysis. “It might be possible,” said Coleman, “to use the antisense RNA amplification method we use for small amounts of starting material, but that would introduce the potential problem of whether the aRNA would extend 5' enough to include the regions containing mutations. Since the authors have a defined target gene it seems to me that the optimal way to improve spatial definition would be via in situ hybridization, with probes constructed to reveal the mutations described.” -Tom Fagan.

References: Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS. Regional analysis of p53 mutations in rheumatoid arthritis synovium. PNAS 2002 July 23;99:10025-10030. Abstract

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  1. 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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  1. . Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10025-30. PubMed.

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  1. . Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10025-30. PubMed.

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  1. . Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10025-30. PubMed.