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bioRxiv · 10.1101/2024.12.11.627854

The intersection of inflammation and DNA damage as a novel axis underlying the pathogenesis of autism spectrum disorders

lizarraga, s. B.·Jhanji, M.·Krall, C. L.·Guevara, A.·Yoon, B.·Mathew, S.·Boccuto, L.
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Abstract

Autism spectrum disorders (ASD) affects 1 in 36 children and is characterized by repetitive behaviors and difficulties in social interactions and social communication. The etiology of ASD is extremely heterogeneous, with a large number of ASD cases that are of unknown or complex etiology, which suggests the potential contribution of epigenetic risk factors. In particular, epidemiological and animal model studies suggest that inflammation during pregnancy could lead to an increased risk of ASD in the offspring. However, the molecular mechanisms that contribute to ASD pathogenesis in relation to maternal inflammation during pregnancy in humans are underexplored. Several pro-inflammatory cytokines have been associated with increased autistic-like behaviors in animal models of maternal immune activation, including IL-17A. Using a combination of ASD patient lymphocytes and stem cell-derived human neurons exposed to IL-17A we discovered a shared molecular signature that highlights a metabolic and translational node that could lead to altered neuronal excitability. Further, our work on human neurons brings forward the possibility that defects in the DNA damage response could be underlying the effect of IL-17A on human excitatory neurons, linking exacerbated unrepaired DNA damage to the pathogenicity of maternal inflammation in connection to ASD.

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lizarraga, s. B., Jhanji, M., Krall, C. L., Guevara, A., Yoon, B., Mathew, S., Boccuto, L.. 2024-12-11. The intersection of inflammation and DNA damage as a novel axis underlying the pathogenesis of autism spectrum disorders. https://doi.org/10.1101/2024.12.11.627854

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