Crosstalks between DNA damage response and retroelements activity in the pathogenesis of Aicardi-Goutières Syndrome

The Aicardi-Goutieres syndrome (AGS) is a rare genetic disease causing several neurological symptoms and chilblain-like skin lesions. AGS is considered an interferonopathy because high levels of interferon-alfa are detected in the cerebro-spinal fluid of patients. AGS diagnosis at birth is thus difficult since the symptoms may be confused with a viral in utero infection. AGS seems to be caused by unscheduled activation of the innate immunoresponse, the major defense against viral infection, which is based on sensing viral nucleic acids. The same sensors on the innate immune response, however, are responsible of certain human autoimmunity diseases, as it is likely the case for AGS. Indeed, causative AGS mutations have been identified in 7 genes involved in the metabolism/sensing of nucleic acids. Recent molecular studies indicate that these mutations affect the correct metabolism of retroelements which represent a large percentage of the human genome. Moreover, AGS mutations have been also linked to chronic activation of the DNA damage response. The interconnections between these two processes are still unclear and represent the major focus of this proposal. We have demonstrated the the function of the RNase H2 complex, which is altered in more than 60% of the AGS patients, is conserved from yeast to man, suggesting that this genetically amenable model system may be useful to gain better insights on the pathogenesis of AGS. We will produce and characterize cell lines of the nervous and immunological system starting from pluripotent stem cells (iPSC) derived from AGS patients. We also plan to use next generation sequence strategies to connect the different types of nucleic acids present in the cytoplasm of these cells with the innate immune response and AGS pathogenesis. Our results will shed light on AGS and other autimmune diseases and may identify potential targets for therapeutic intervention.