Abstract
Purpose :
Parthanatos is a caspase-independent cell death pathway that is distinct from apoptosis, necroptosis, and pyroptosis. Parthanatos is mediated by rapid overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) that results in large-scale DNA fragmentation and cell death distinct from small-scale DNA fragmentation observed during apoptosis. Because parthanatos has been associated with a variety of diseases including Parkinson’s disease, cardiovascular disease, and diabetes, we investigated the possibility that this unique cell death pathway might also operate during the pathophysiology of AIDS-related cytomegalovirus retinitis using an experimental animal model of experimental MCMV retinitis in mice with MAIDS. We therefore performed in vivo studies to test the hypothesis that PARP-1, essential for initiation of parthanatos, is stimulated intraocularly during onset and development of MAIDS-related MCMV retinitis.
Methods :
The left eyes of groups of C57BL/6 mice with MAIDS who are susceptible to MCMV retinitis were injected subretinally with MCMV. Right eyes injected subretinally with maintenance medium only served as controls. At 3, 6, and 10 days postinfection (dpi), left and right eyes were collected and compared for stimulation of PARP-1 mRNA and protein production by quantitative RT-PCR assay and western blot analysis, respectively.
Results :
MCMV-infected eyes of MAIDS mice initially showed significant amounts of PARP-1 mRNA at 3 dpi when compared with uninfected control eyes, but PARP-1 mRNA levels rapidly decreased at 6 and 10 dpi. MCMV-infected eyes of MAIDS mice also initially showed simultaneous stimulation of uncleaved PARP-1 protein at 3 dpi, whereas cleaved PARP-1 protein was detected at highest amounts at 10 dpi.
Conclusions :
Stimulation of PARP-1 mRNA production and uncleaved PARP-1 protein were detected soon after subretinal MCMV infection of eyes of MAIDS mice that progressed to stimulation of PARP-1 protein at time of retinitis development. Our findings suggest an involvement of PARP-1 in the pathogenesis of MAIDS-related MCMV retinitis, possibly during parthanatos. To further explore the possible role of PARP-1 in parthanatos, future studies will investigate other parthanatos-associated events such as induction of intraocular reactive oxygen and large-scale DNA fragmentation.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.