Promyelocytic Leukemia Nuclear Bodies Provide a Scaffold for Human Polyomavirus JC Replication and Are Disrupted After Development of Viral Inclusions in Progressive Multifocal Leukoencephalopathy

• Published in: Journal of neuropathology and experimental neurology 2008-04, Vol.67 (4), p.299-308
• Main Authors: Shishido-Hara, Yukiko, Higuchi, Kayoko, Ohara, Sinji, Duyckaerts, Charles, Hauw, Jean-Jacques, Uchihara, Toshiki
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Capsid Proteins - metabolism; Cercopithecus aethiops; COS Cells - ultrastructure; COS Cells - virology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Humans; Inclusion Bodies, Viral - diagnostic imaging; Inclusion Bodies, Viral - metabolism; Inclusion Bodies, Viral - pathology; JC Virus - pathogenicity; JC Virus - physiology; JC Virus - ultrastructure; Leukoencephalopathy, Progressive Multifocal - etiology; Leukoencephalopathy, Progressive Multifocal - pathology; Leukoencephalopathy, Progressive Multifocal - virology; Male; Medical sciences; Microscopy, Electron, Transmission - methods; Middle Aged; Neoplasm Proteins - metabolism; Neurology; Nuclear Proteins - metabolism; Polyomavirus; Promyelocytic Leukemia Protein; SUMO-1 Protein - metabolism; Transcription Factors - metabolism; Transfection; Tumor Suppressor Proteins - metabolism; Ubiquitin - metabolism; Ultrasonography; Virus Replication - physiology
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e31816a1dd3

Progressive multifocal leukoencephalopathy is a fatal demyelinating disorder due to human polyomavirus JC infection in which there are viral inclusions in enlarged nuclei of infected oligodendrocytes. We report that the pathogenesis of this disease is associated with distinct subnuclear structures known as promyelocytic leukemia nuclear bodies (PML-NBs). Postmortem brain tissues from 5 patients with the disease were examined. Affected cells with enlarged nuclei contained distinct dot-like subnuclear PML-NBs that were immunopositive for PML protein and nuclear body protein Sp100. Major and minor viral capsid proteins and proliferating cell nuclear antigen, an essential component for DNA replication, colocalized with PML-NBs. By in situ hybridization, viral genomic DNA showed dot-like nuclear accumulation, and by electron microscopy, virus-like structures clustered in subnuclear domains, indicating that PML-NBs are the site of viral DNA replication and capsid assembly. Molecules involved in the ubiquitin proteosome pathway (i.e. ubiquitin and small ubiquitin-like modifier 1) did not accumulate in the nuclei with viral inclusions, indicating that cell degeneration may not be dependent on this pathway. When viral progeny production was advanced, PML-NBs were disrupted. These data suggest that1) PML-NBs allow for efficient viral propagation by providing scaffolds, 2) disruption of PML-NBs is independent of the ubiquitin-proteasome pathway, and 3) this disruption probably heralds oligodendrocyte degeneration and the resulting demyelination.