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Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models

Periodic Reporting for period 4 - REVERSEAUTISM (Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models)

Reporting period: 2022-04-01 to 2022-09-30

The Centers for Disease Control estimated that Autism spectrum disorders (ASD) affect 1 in 68 children with males being affected 4 to 6 times more than females. In spite of strong public and scientific interest, making a diagnosis of autism is challenging due to the absence of common clinical observations and biomarkers. Therefore, ASDs are often diagnosed late during infancy (Daniels et al., 2013). Due to the developmental character (and the late diagnosis), ASDs have been considered a group of non-curable disorders. In the majority of the cases, children with autism are affected by other syndromes, including intellectual disability (40-60% of ASD cases) and epilepsy (20-30% of ASD cases), indicating that these conditions may share common molecular mechanisms. Any advancement in understanding the pathophysiology underlying ASDs will have a great impact on epilepsy and intellectual disability research. Also, since many ASD cases are caused by mutations in private genes (i.e. mutated in a single patient), understanding how specific genetic mutations lead to ASDs will be very valuable to interpret future genetic data. We are working to understand how mutations in specific genes lead to ASDs and impact brain development. In particular our work focus on 1) the role of mutations in genes encoding for protein associated with regulating or sensing branched chain amino acids levels and 2) in modelling ASD associated mutations in human 3D cellular models.
Our work aims to elucidate basic molecular mechanisms affected in individuals carrying genetic mutations associated with autism spectrum disorders. In particular in this project we are focused on the study of autism and neurodevelopmental problems associated with abnormal amino acid (AA) homeostasis, like in patients with mutations in the BCKDK or SLC7A5 gene. SLC7A5 encodes a large neutral amino acid transporter called LAT1, which is responsible for regulating the branched chain amino acid homeostasis in the brain. Patients harbouring homozygous missense mutations in SLC7A5 are on the autism spectrum (ASD) and present with motor deficits and microcephaly. Employing a series of mouse models we discovered that a reduction of branched chain amino acid (i.e. valine, leucine and isoleucine) levels leads to abnormal protein synthesis in the brain and several neurological abnormalities. Moreover, our group was able to show that intracerebroventricular administration of leucine and isoleucine ameliorate the molecular and behavioral phenotypes observed in Slc7a5 mutant mice. Furthermore, we have found that at early stages of brain development a reduction of branched chain amino acid levels leads to abnormal cortical development. We are currently, investigating the exact biological processes affected by mutations in BCKDK and SLC7A5.
In a parallel effort, we are exploring the use of stem cell-derived 3-D cerebral models (i.e. cerebral organoids) to study the effect of mutations associated with autism. In the first phase of the project, we generated a number of isogeneic human embryonic stem cell lines carrying mutations in high-risk autism genes and analyzed the derived cerebral organoids employing a variety of techniques to reveal cellular and molecular abnormalities.
Further description of the ERC-related work can be found here
Our study revealed significant roles of BCAA in neurons and their importance during critical stages of brain development. This not only advances our understanding of BCAA in the brain but also emphasizes the need for early intervention in patients with BCKDK and SLC7A5 mutations affecting BCAA levels. Additionally, our work on cerebral organoids provides a proof of concept for studying the impairment of ASD-associated genes during vulnerable periods of brain development. Overall, our project contributes to the knowledge of human brain development, the pathophysiology of ASD, and potential treatment approaches.

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