Cell Death Signaling

Neuroimmunomodulatory role of gastrointestinal infection in ADNP manifestations

Autism Spectrum Disorders (ASD) display a wide array of symptoms including deficits in social communication,impaired cognition, and anxious and repetitive behaviors, which affects 1% of the human population. To date ADNP is one of the most frequent ASD-associated genes (~0,2% of all ASD cases). ADNP truncation mutationscause an autosomal-dominant autism spectrum Helsmoortel-Van der Aa syndrome with highly variable clinical presentations of autism, intellectual disability, dysmorphic facial features, deficits in multiple organ systems andpatients frequently suffer of comorbidities including increased susceptibility to inflammation, or gastrointestinal disturbances. In order to understand how Adnp truncations provoke this broad spectrum of clinical ASD manifestations a novel genetic frameshift mutation Adnp-mut mouse model was generated, of which neurologicalASD manifestations align with observations in Helsmoortel-Van der Aa syndrome (HVDAS) patients, including exacerbated anxiety, repetitive behavior and cognitive deficits and altered expression of synaptic plasticity genes.Based on preliminary studies in our Adnpmut mouse model, our core hypothesis in this proposal is that Adnp mutations cause altered epigenetic profiles which trigger DNA damage inflammasome responses, leading to neuroinflammation that perpetuates ASD development. Given the high prevalence of gastrointestinal problems in patients with the ADNP-related disorder and the relevance of the gut-brain axis in neuropathology, we expect that disturbances in gut homeostasis may exacerbate inflammation and amplify severity of ASD symptoms in Adnp-mut mice. Therefore, in this project, we will test our core hypothesis in naïve Adnp-mut mice as well as after a dysbiosis and inflammation-provoking intestinal infection. Specifically, we will :

  • Define the contribution of neuroinflammation in ADNP-ASD pathology
  • Define the contribution of Aim2 inflammasome signaling in ADNP-ASD pathology 
  • Define epigenetic malfunctions of Aim2 inflammasome signaling in ADNP-ASD pathology 
  • Evaluate viral and peptide-based therapeutics to alleviate inflammation and ameliorate ADNP-ASD manifestations. 

Demonstrating how gastrointestinal infections promote epigenetic DNA damage which exacerbates neuroinflammation and ASDsymptoms will significantly broaden our understanding of highly variable HVDAS manifestations. From a societalpoint of view, a proof-of-concept that a gut infection can aggravate ADNP syndromic autism will open insights for clinicians as well as for patients themselves in how to understand, prevent or manage ASD symptoms or other neuroplasticity pathologies via gut-brain intervention strategies.

Researcher(s)