Janoshazi A, Sellal F, Marescaux C, Danion JM, Warter JM, de Barry J. Alteration of protein kinase C conformation in red blood cells: a potential marker for Alzheimer's disease but not for Parkinson's disease. Neurobiol Aging. 2006 Feb;27(2):245-51. PubMed.
Recommends
Please login to recommend the paper.
Comments
Banner Research Institute
Alzheimer’s Is Not a Brain Disease
In this paper, Janoshazi et al. describe alterations of protein kinase C in erythrocytes of Alzheimer patients that distinguish them from erythrocytes of controls with “close to 100 percent” sensitivity and specificity. Their data also distinguish AD from nondemented Parkinson disease with p In 1993, Chen and Poenie synthesized fluorescent derivatives of bisindolylmaleimide inhibitors of protein kinase C. Several of these, including Fim-1, were found to act as ATP-competitive catalytic site inhibitors. This Chen and Poenie paper used these compounds to describe intracellular translocation of PKC as activation of PKC was manipulated by PMA. They also describe mitochondrial staining. Subsequently, Janoshazi and de Barry (1999) also reported that Fim-1 fluorescence depended on the activation state of PKCα. In this 1999 paper they inferred that Fim-1 fluorescence was detecting conformational change in PKCα following treatment of PKC with a phorbol ester (TPA).
In the current 2005 paper, Janoshazi et al. differentiate erythrocytes of AD (N = 33) from controls (N = 25) on the basis of alteration of calculated spectral distortion index (SDI) after treating erythrocytes with either TPA or staurosporine. The SDI was based on the ratio of fluorescent emission at 518 nm to total emission. Their Figure 2 shows no overlap between AD and control samples in SDI following treatment of erythrocytes with staurosporine and minimal overlap (one control in AD space) following treatment with TPA.
The cell biological significance of this finding is not yet clearly established. However, Kim et al. (2004) have reported that oligomeric Aβ inactivated membranous PKC and activated cytosolic PKC. Nevertheless, these data do dramatically demonstrate that AD affects PKC in erythrocytes of the peripheral circulation. This is not the first demonstration of altered rbc in AD. For example, Kay and Goodman (1997) found altered band 3 protein in AD rbc. And, more recently, Rogers et al. have found rbc interaction with Aβ (personal communication). A far more extensive literature has described effects of AD on other peripheral cells, including leukocyte subtypes and platelets. Fibroblasts have also been shown to be affected in AD. And, many of these effects on peripheral cells have involved systems related to cellular stress, inflammatory responses, and the cell cycle—all of which have also been shown to be affected in the brain in AD.
These accumulating data indicate striking similarities in the effects of AD on brain cells and on peripheral cells. Whether AD pathophysiology is exclusively the province of the brain to be reported secondarily by peripheral cells, or whether AD is a systemic disease that affects multiple cell types throughout the body through similar mechanisms remains to be conclusively determined. Current data suggest the latter.
References:
Chen CS, Poenie M. New fluorescent probes for protein kinase C. Synthesis, characterization, and application. J Biol Chem. 1993 Jul 25;268(21):15812-22. PubMed.
Janoshazi A, de Barry J. Rapid in vitro conformational changes of the catalytic site of PKC alpha assessed by FIM-1 fluorescence. Biochemistry. 1999 Oct 5;38(40):13316-27. PubMed.
Kay MM, Goodman J. Brain and erythrocyte anion transporter protein, band 3, as a marker for Alzheimer's disease: structural changes detected by electron microscopy, phosphorylation, and antibodies. Gerontology. 1997;43(1-2):44-66. PubMed.
Kim HJ, Kim JH, Chae SC, Park YC, Kwon KS, Hong ST. Soluble oligomeric Abeta disrupts the protein kinase C signaling pathway. Neuroreport. 2004 Mar 1;15(3):503-7. PubMed.
Yale University School of Medicine
I can't say that I agree with Paul Coleman's evaluation of this work. The method of analysis is quite convoluted, and it is not at all clear what is causing the difference in fluorescence intensity at particular wave lengths. It is very unlikely that the authors are sampling conformational changes in PKC. If the authors can rule out non-specific effects of medications in AD patients, it may be worth looking at the basis for the differences they report, but I am not encouraged by what has been presented.
Banner Research Institute
Reply to Vincent Marchesi
My review stated that they "INFERRED that Fim-1 fluorescence was detecting conformational change" for I, too, felt that evidence for conformational change was lacking and that "The cell biological significance of this finding is not yet clearly established." I agree with Vin Marchesi that the method of analysis was convoluted. Nevertheless, the fact remains that Janoshazi et al. have described a striking alteration in AD red blood cells and that others (alluded to in my comments) have also found AD red blood cells to differ from controls. Certainly the Janoshazi et al. work deserves replication, but it contributes further evidence to suggest that AD may not be the province of the brain alone. I find no disagreement between my evaluation and Vin Marchesi's comment.
Make a Comment
To make a comment you must login or register.