DNA amplification in glial cells of progressive multifocal leukoencephalopathy: an image analysis study.
ABSTRACT JC virus (JCV), the agent of progressive multifocal leukoencephalopathy (PML), has been shown by both immunohistochemistry and flow cytometry to be associated with p53 protein stabilization. Since stabilization/inactivation of p53 is associated with the development of genomic instability, abnormal cell DNA contents are to be expected in JCV-infected cells of PML. This work explores that possibility by image analysis evaluation of DNA content in PML-infected oligodendrocytes and bizarre astrocytes. Brain paraffin sections of PML lesions from five adult male patients with the acquired immune deficiency syndrome (AIDS) were treated with the Feulgen technique to obtain a stochiometric staining of DNA and analyzed with a microscope image processor. Inclusion-bearing oligodendrocytes exhibited near tetraploid DNA indices in each of the five cases, whereas atypical astrocytes were in the hypertetraploid range in all cases and were polyploid in four instances. This evidence of DNA amplification in PML glial cells is congruent with the functional abolition of p53 protein in association with JCV infection and lends further support to the role of p53 as a keeper of diploid status and guardian of genomic stability.
- SourceAvailable from: Armine Darbinyan[show abstract] [hide abstract]
ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the CNS caused by infection of glial cells with the polyomavirus, JCV. Here we report that genomic stability and DNA repair are significantly dysregulated by JCV infection of human astrocytes. Metaphase spreads exhibited increased ploidy correlating with duration of infection. Increased micronuclei formation and phospho-Histone2AX expression also indicated DNA damage. Western blot analysis revealed perturbation in expression of some DNA repair proteins including a large elevation of Rad51. Immunohistochemistry on clinical samples of PML showed robust labeling for Rad51 in nuclei of bizarre astrocytes and inclusion body-bearing oligodendrocytes that are characteristic of JCV infection. Finally, in vitro end-joining DNA repair was altered in extracts prepared from JCV-infected human astrocytes. Alterations in DNA repair pathways may be important for the life cycle of JCV and the pathogenesis of PML.Virology 08/2007; 364(1):73-86. · 3.37 Impact Factor
- Revista de neurologia 01/2008; 47(5):231-235. · 1.18 Impact Factor
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ABSTRACT: The term progressive multifocal leukoencephalopathy (PML) denotes a demyelinating neurological disease caused by oligodendrocyte destruction produced by reactivation of human polyomavirus JC, usually acquired in childhood. The advent of acquired immunodeficiency syndrome (AIDS) has contributed to the marked increase in the frequency of this disease and to incomplete discovery of the complex and close molecular relations between JC and human immunodeficiency virus (HIV). Clinical manifestations are nonspecific and are typical of any demyelinating disease, although PML is more aggressive and has a poor prognosis. Definitive diagnosis is based on histological analysis, but neuroimaging and polymerase chain reaction for JC virus in cerebrospinal fluid can also be used. There is no curative therapy. Autoimmune diseases and, recently, iatrogenic damage by immunosuppressors and monoclonal antibodies, are other causes of this disease.Seminarios de la Fundación Española de Reumatología 01/2009; 10(3):91-99.