Abstract
Several findings suggest that Herpes simplex virus-1 (HSV-1) infection plays a role in the neurodegenerative processes that characterize Alzheimer’s disease (AD), but the underlying mechanisms have yet to be fully elucidated. Here we show that HSV-1 productive infection in cortical neurons causes the accumulation of DNA lesions that include both single (SSBs) and double strand breaks (DSBs), which are reported to be implicated in the neuronal loss observed in neurodegenerative diseases. We demonstrate that HSV-1 downregulates the expression level of Ku80, one of the main components of non-homologous end joining (NHEJ), a major pathway for the repair of DSBs. We also provide data suggesting that HSV-1 drives Ku80 for proteasomal degradation and impairs NHEJ activity, leading to DSB accumulation. Since HSV-1 usually causes life-long recurrent infections, it is possible to speculate that cumulating damages, including those occurring on DNA, may contribute to virus induced neurotoxicity and neurodegeneration, further suggesting HSV-1 as a risk factor for neurodegenerative conditions.
Highlights
Unrepaired DNA lesions and deficit in pathways repairing DNA have been documented in several neurodegenerative diseases, including Alzheimer’s disease (AD; Robison et al, 1987; Mullaart et al, 1990; Adamec et al, 1999; Shackelford, 2006; Weissman et al, 2007)
Double labeling of Herpes simplex virus-1 (HSV-1)-infected neurons with anti-γH2AX and anti-ICP8 antibodies showed that 24 h p.i. γH2AX foci accumulate in areas surrounding the viral replicative compartments (Figure 1C), indicating that DNA lesions occur on marginated neuronal chromatin, whereas viral genome was unaffected
We show that HSV-1 productive infection in neurons causes an accumulation of DNA lesions (SSBs and double strand breaks (DSBs)) and affects expression of Ku80 and non-homologous-end joining pathway (NHEJ) repair activity
Summary
Unrepaired DNA lesions and deficit in pathways repairing DNA have been documented in several neurodegenerative diseases, including Alzheimer’s disease (AD; Robison et al, 1987; Mullaart et al, 1990; Adamec et al, 1999; Shackelford, 2006; Weissman et al, 2007). DSBs are repaired in neurons mainly through the non-homologous-end joining pathway (NHEJ; Lieber et al, 2003) which relies on the DNA-dependent protein kinase (DNA-PK) complex. This complex is formed by the 470-kDa catalytic subunit, DNA-PKcs, and the Ku70/80-heterodimer. HSV-1 Affects NHEJ Pathway in Neurons repair and ligation, recruiting and activating DNA-PKcs and other core proteins of NHEJ pathways (Smith and Jackson, 1999; Mills et al, 2003; Weterings and Chen, 2008; De Zio et al, 2012). We previously reported that DNA-PK activity is impaired following acute exposure to beta amyloid peptides (Aβs), important players in AD pathogenesis and ROS production (Cardinale et al, 2012), indicating a possible cause for NHEJ impairment observed in AD
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