Genetic studies have identified a large number of genes that increase the risk for autism. Many of these risk genes function to regulate the genome in the developing brain. Anne West aims to identify common regulatory mechanisms used by many ASD risk genes that may explain convergent effects on gene regulation during neurodevelopment.
In this pilot study, Pierre Vanderhaeghen and his team aim to explore the intricate connections between ASD, mitochondrial function, and human neuronal development, with a specific focus on developmental timing. Innovative tools, including an in vitro model for studying mitochondrial morphology, dynamics, and function and an in vivo xenotransplantation model of human cortical neurons, will be used to achieve this. The investigation seeks to understand how mitochondrial dynamics and metabolism contribute to the pathology of ASD-linked mutations in genes such as MECP2 and SYNGAP1.
In this project, Joris de Wit and colleagues plan to assess the role of ASD risk genes in the development of a specific thalamocortical circuit, connecting the posterior medial nucleus (POm) of the thalamus and intratelencephalic layer 5 pyramidal neurons (IT L5 PNs) in the cortex. This circuit is of particular interest due to its potential link to sensory processing, a function often found to be altered in autistic individuals.
Marta Biagioli and colleagues intend to provide further proof of the efficacy of RNA therapy, proposing SINEUP technology as a new RNA-based tool for the treatment of genetic ASDs. Her lab intends to share validated SINEUP reagents with the ASD community so that SINEUP therapeutic properties could be further analyzed to streamline the development of these molecules to the clinic.
To advance our understanding of the epigenetic contribution to autism, Zhaolan (Joe) Zhou aims to test a hypothesis that the transcription of broad enhancer-like chromatin domain (BELD) genes is particularly sensitive to mutations in chromatin genes and that deregulation of those BELD genes underlies the pathogenesis of autism. The ultimate goal is to provide a foundation to identify possible points of biological convergence and promote mechanism-based therapeutic development.
One of the overall goals of autism research is to discover convergent mechanisms underlying the condition across individuals. With this goal in mind, Eirene Markenscoff-Papadimitriou aims to look for common mechanisms of dysfunction that result from mutations in two autism risk genes, POGZ and ADNP. Knock-out mouse models, as well as stem-cell derived neurons lacking these two genes, will be studied to assess what impact the loss of these two genes has on cortical gene expression and chromatin state.
Brain imaging in children and adults with autism spectrum disorder (ASD) have identified excessive local connectivity and long-range dysconnectivity in the cerebral cortex. In this project, Kartik Pattabiraman aims to use single cell-level transcriptomic and viral circuit tracing approaches to spatiotemporally characterize mouse cortical subplate neurons and characterize their role in cortical circuit assembly and disruption associated with ASD.
The SFARI gene database lists both GIGYF1 and GIGYF2 as high confidence risk factors, as both have a probability of loss of function intolerance (pLI) score of 1. It is our hypothesis that GIGYF1/2 mutations disrupt the function of the GIGYF1/2-4EHP translation repression, thus resulting in dysregulation of protein synthesis which causes impaired synaptic function and susceptibility to behavioral impairments. We will use cell-specific GIGYF1/2 conditional knockout mice, which will be subjected to a battery of behavioral tests, ribosome profiling and proteomics to investigate the mice for behavioral impairments and changes in translational efficiency. Our goal is to provide novel insight into the molecular mechanisms mediating ASD-like behaviors via GIGYF1/2 and establish a preclinical basis for therapeutic intervention in ASD patients.
The tremendous genotypic and phenotypic diversity in ASD has made it extremely challenging to pinpoint causal mechanisms, distinguish the effects of individual genetic variants, stratify patients into subtypes and develop treatments. In the current project, Randall J. Platt plans to profile patient-specific CHD8 variants in human-derived stem cells and induced neurons. The overall aim is to functionally dissect CHD8 mutations and help prioritize convergent/divergent mechanisms for future studies.