Research Emanuela Pasciuto

Abstract

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 mutations cause 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 and patients 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 Adnpmut mouse model was generated, of which neurological ASD 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 Adnpmut mice. Therefore, in this project, we will test our core hypothesis in naïve Adnpmut mice as well as after a dysbiosis- and inflammation-provoking intestinal infection. Specifically, we will 1) Define the contribution of neuroinflammation in ADNP-ASD pathology, 2) Define the contribution of Aim2 inflammasome signaling in ADNP-ASD pathology 3) Define epigenetic malfunctions of Aim2 inflammasome signaling in ADNP-ASD pathology 4) 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 ASD symptoms will significantly broaden our understanding of highly variable HVDAS manifestations. From a societal point 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)

• Promoter: Vanden Berghe Wim
• Co-promoter: Kooy Frank
• Co-promoter: Pasciuto Emanuela
• Co-promoter: Wullaert Andy

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project

Abstract

During the last decade, impressive effects of environmental enrichment have been reported in a wide range of brain disorders both in rodents and humans. An enriched environment (EE) in experimental research is a manipulation of the standard housing condition that provides animals with increased levels of multisensory stimulation, physical activity and social interactions. Prolonged housing in EE promotes neuronal function, enhances learning and memory, and reduces stress and inflammatory responses. Alongside the neurological effects, the EE has a modulating effect upon the immune response. The mechanisms underlying the crosstalk between external stimulations and the neuro-immune axis are not yet understood. This project not only will allow us to start to mechanistically decipher how experience influences the interactions between the neurons and the immune system in rodents but also will open the opportunity to identify novel targets for the development of therapeutics that mimic and/or enhance the beneficial effects of cognitive therapy in humans.

Researcher(s)

• Promoter: Pasciuto Emanuela

Research team(s)

• VIB CMN - Neuroimmunology

Project type(s)

• Research Project

Abstract

Loss-function mutations in the Activity-dependent neuroprotective protein (ADNP) gene have been linked to the Helsmoortel-Van der Aa Syndrome, a complex neurological disorder characterized by autism and intellectual disability. The Adnp mutant mice recapitulate key hallmark of autism spectrum disorders including learning deficit, increased anxiety and repetitive behavior. ADNP is involved in brain development and neuroprotection. In addition to the neuroprotective effect, ADNP also has immunomodulatory effects. ADNP is expressed in cells of the immune system and can suppress the production of pro-inflammatory cytokines. Studies in Multiple Sclerosis have linked ADNP deficiency to reduced regulatory T cell function, an immunomodulatory subset of T cells. A better understanding of the immune changes associated with ADNP deficiency may provide clues to pathological processes and allow to identify biological markers that enable early diagnosis and treatment of ASD. In this project, we will explore the role of ADNP in T cells function, to this end will perform in depth characterization of the molecular and cellular signature acquired by T cells and microglia cell populations in the mutant mice. We hypothesize that in Adpn mice defective function of Regulatory T cells exacerbate the pathology. We will use a tailored gene therapy to specifically expand Regulatory T cells in the brain and evaluate the effect on the behaviour of the Adpn mutant mice

Researcher(s)

• Promoter: Pasciuto Emanuela

Research team(s)

• VIB CMN - Neuroimmunology

Project type(s)

• Research Project