Function of the Co-chaperone STIP1 in Neurodevelopment: 3D-Platforms to Model Autism Spectrum Disorder

• Grant number: 24/14288-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2024
• End date: November 30, 2027
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Camila Felix de Lima Fernandes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Autism Spectrum Disorder (ASD) is believed to affect 1 in 100 children worldwide and encompasses a range of neurodevelopmental conditions characterized by impairments in social interaction, communication deficits, and stereotyped behaviors. ASD's etiology involves a complex interplay of genetic, epigenetic, metabolic, immunological and environmental factors. Its heterogeneity further challenges diagnosis and treatment, highlighting the need for reliable biomarkers and a deeper understanding of its underlying mechanisms. A specific subtype of ASD, Maternal Autoantibodiesrelated ASD (MAR-ASD), involves maternal autoantibodies (MAUAbs) targeting fetal brain tissue. These autoantibodies, including those against the Stress-inducible Phosphoprotein 1 (STIP1), are associated with more severe forms of ASD. STIP1, a cochaperone for the heat shock proteins HSP70 and HSP90, plays a critical role in neurodevelopment through its interaction with the cellular prion protein. This complex is essential for protein homeostasis, neuritogenesis, neuronal protection, and memory formation. STIP1 knockout in mice results in early embryonic lethality and impaired neural tube formation, underscoring its importance in early development. However, the specific effects of STIP1 knockdown on human neurodevelopment and its interaction with maternal autoantibodies in ASD are not well understood. This project aims to comprehensively investigate the functions of STIP1 in neurodevelopment and assess the impact of anti-STIP1, a type of MAUAbs, on human models, by using 3D platforms to model neural development and brain function. Furthermore, we aim to initiate the study of MAR-ASD in Brazil, by testing the prevalence of MAUAbs in a cohort of mothers of ASD children. Through this project, we will elucidate the molecular pathways modulated by STIP1 and its partners in the context of neurodevelopment and ASD, providing insights into potential biomarkers and therapeutic targets for this disorder.