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Journal of Virology, February 2008, p. 1748-1758, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02014-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hippocampal Poly(ADP-Ribose) Polymerase 1 and Caspase 3 Activation in Neonatal Bornavirus Infection{triangledown}

Brent L. Williams, Mady Hornig, Kavitha Yaddanapudi, and W. Ian Lipkin*

Center for Infection and Immunity, Mailman School of Public Health of Columbia University, New York, New York

Received 12 September 2007/ Accepted 19 November 2007

Infection of neonatal rats with Borna disease virus results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus, cerebellum, and cortex (neonatal Borna disease [NBD]). In the NBD rat hippocampus, dentate gyrus granule cells progressively degenerate. Apoptotic loss of granule cells in NBD is associated with accumulation of zinc in degenerating neurons and reduced zinc in granule cell mossy fibers. Excess zinc can trigger poly(ADP-ribose) polymerase 1 (PARP-1) activation, and PARP-1 activation can mediate neuronal death. Here, we evaluate hippocampal PARP-1 mRNA and protein expression levels, activation, and cleavage, as well as apoptosis-inducing factor (AIF) nuclear translocation and executioner caspase 3 activation, in NBD rats. PARP-1 mRNA and protein levels were increased in NBD hippocampi. PARP-1 expression and activity were increased in granule cell neurons and glia with enhanced ribosylation of proteins, including PARP-1 itself. In contrast, levels of poly(ADP-ribose) glycohydrolase mRNA were decreased in NBD hippocampi. PARP-1 cleavage and AIF expression were also increased in astrocytes in NBD hippocampi. Levels of activated caspase 3 protein were increased in NBD hippocampi and localized to nuclei, mossy fibers, and dendrites of granule cell neurons. These results implicate aberrant zinc homeostasis, PARP-1, and caspase 3 activation as contributing factors in hippocampal neurodegeneration in NBD.

* Corresponding author. Mailing address: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, 722 West 168th Street, Room 1801, New York, NY 10032. Phone: (212) 342-9033. Fax: (212) 342-9044. E-mail: wil2001{at}columbia.edu

{triangledown} Published ahead of print on 5 December 2007.

Journal of Virology, February 2008, p. 1748-1758, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02014-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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