- Awarded: 2024
- Award Type: Pilot
- Award #: SFI-AN-AR-Pilot-00005813
Most forms of autism spectrum disorder (ASD) are thought to be caused by disruptions in molecular processes involved in gene regulation or synaptic function. However, emerging evidence suggests that mitochondrial and metabolic dysfunction may also be affected in some of these conditions1–3. In this study, Pierre Vanderhaeghen and colleagues plan to investigate the mechanistic links between mitochondria and ASD in human cortical neurons, focusing on two specific forms of ASD caused by genetic alterations in MECP2 or SYNGAP1.
First, Vanderhaeghen and his team plan to determine whether and how mitochondrial dynamics and metabolism are altered in human cortical neurons derived from PSC (from patients iPSCs or control ESC, engineered with CRISPR-Cas technology to provide pathogenic mutants or isogenic controls) carrying ASD-linked pathogenic mutations in MECP2 or SYNGAP1. They aim to analyze mitochondrial morphology and metabolism with unprecedented temporal and cellular resolution in human cortical neurons of the different genotypes. Next, they plan to functionally examine the causal relationships between ASD gene disruption and mitochondrial function. To achieve this, they aim to manipulate mitochondria pharmacologically (in vitro) and/or genetically (in vivo) in human cortical neurons and analyze their morphological and functional development in vivo, following xenotransplantation in the mouse brain.
This project will provide novel insights on mitochondria during human neuronal development in relation to ASD molecular and cellular conditions. Vanderhaeghen’s team will develop a robust pipeline for analyzing metabolic defects in human neuronal development, which can be applied to the pathogenic mechanisms of other forms of ASD. If successful, this project will pave the way for identifying molecular mechanisms linking metabolism and ASD pathogenesis, with potentially important implications for diagnosis and treatment.