SHANK3-environment interactions and neurodegenerative processes: Mechanistic insights using chimeric organoids

• Grant number: 25/00191-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2025
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Rita dos Santos e Passos Bueno
• Grantee: Elisa Varella Branco
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID

Abstract

Phelan-McDermid Syndrome (PMS), a synaptopathy associated with Autism Spectrum Disorder (ASD) and intellectual disability, is caused by loss-of-function alterations in the SHANK3 gene, which is critical for cortical development and the maintenance of brain connectivity. In addition to neurodevelopmental delays, individuals with PMS frequently experience episodes of cognitive and neurological regression, which may progress to neurodegenerative-like phenotypes and early-onset dementia in adulthood. The underlying causes of these episodes and how SHANK3 deficiency contributes to these processes remain poorly understood. While the role of SHANK3 in synaptogenesis is well-documented, findings from our group have expanded this understanding by demonstrating its involvement in processes such as neurogenesis and cell cycle regulation. These functions overlap with those of genes classically linked to neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. Environmental factors that promote neuroinflammation, particularly through the activation of pro-inflammatory cytokines, play a significant role in both neurodevelopmental disorders and neurodegenerative conditions. This project aims to investigate how pathogenic variants in SHANK3 alter cortical cellular organization and composition, contributing-along with neuroinflammatory factors-to increased vulnerability to neurodegenerative phenotypes. To address this, we will employ chimeric brain organoids as an experimental model, integrating cells from different donors into a single three-dimensional system. These organoids will be analyzed using single-cell RNA sequencing (scRNA-seq) to identify alterations in specific molecular pathways. The study will include organoids carrying SHANK3 variants, PSEN1 variants (positive controls for Alzheimer's disease), and healthy centenarian controls, all of which will be exposed to pro-inflammatory cytokines such as hyper-IL-6 to investigate gene-gene and gene-environment interactions. Based on the scRNA-seq results, we aim to identify molecular pathways linking neurodevelopmental and neurodegenerative processes. These pathways will be further studied in functional experiments to elucidate their roles and interactions. The findings from this study have the potential to significantly advance our understanding of the vulnerability to degenerative phenotypes in genetic conditions such as PMS and to identify critical pathways that could inform the development of personalized therapeutic strategies for neurodevelopmental disorders.