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Regulation of CNS health by the AIM2 Inflammasome

Presenters Name: 
Calli Bellinger
Primary Research Mentor: 
John Lukens
Secondary Research Mentor: 
Elizabeth Frost
2:00 - 2:15
Time of Presentation: 
2019 - 2:00pm to 2:15pm
South Meeting Room
Presentation Type: 
Presentations Academic Category: 
Grant Program Recipient: 
Harrison Undergraduate Research Grant

Genomic integrity is essential to a healthy central nervous system (CNS). While DNA damage, in the form of double-stranded DNA breaks (dsDNA), is common within the CNS as a result of normal neuronal activity and neuronal dieback during development, evidence has shown that the accumulation of DNA damage within the CNS contributes to neurodevelopmental and neurodegenerative disorders. Recent studies in peripheral immune cells have identified key roles for the AIM2 inflammasome (AIM2-I) in the innate immune system in response to DNA damage. AIM2 is an immune-based genomic sensor that responds to cytosolic and nuclear dsDNA. Whether AIM2 plays a role in the recognition of dsDNA in CNS development and homeostasis is currently unknown. Through the use of genetic knockouts of AIM2, Ice (caspase-1), and Gsdmd (gasdermin-D), we tested for behavioral and histological abnormalities. For behavior, we used open field and elevated-plus maze, both of which tests for anxiety-associated behaviors. Histology was performed by using immunohistochemistry (IHC) to look at purkinje cells within the cerebellum along with DNA damage. We found that defects in AIM2-I signaling leads to abnormalities in cerebellar architecture and the development of anxiety-like behavior. Furthermore, the disruption of downstream signaling of the AIM2-I pathway as well as blocking molecules necessary for inflammasome-induced death is sufficient enough to lead to the accumulation of DNA damage within the CNS and result in anxiety-like behavior. In conclusion, understanding how a healthy CNS controls genomic stress may lead to future therapeutic treatments in neurological disorders that stem from DNA damage.