Leveraging human iPSC technology to understand the role of neuroinflammation in 22q11.2 deletion syndrome

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY Chromosome 22q11.2 deletion syndrome (22qDS) is a rare genetic disorder caused by microdeletions of 1-3 MB on chromosome 22 leading to haploinsufficiency of ~50 protein-coding genes and numerous non-coding genes. Genes in the 22q11.2 region encompass a variety of functions, including miRNA processing, mitochondrial metabolism, and protein trafficking which shape cellular function through distinct pathways. At the clinical level, 22qDS manifests in cardiovascular, immune, and nervous system defects. Strikingly, ~25 % of 22qDS patients develop schizophrenia (SCZ) with clinical symptoms mirroring idiopathic SCZ. In particular, while several lines of evidence show that inflammation and microglial hyperactivation contribute to SCZ development through overt synaptic pruning during adolescence and idiopathic SCZ patients display chronic peripheral low- grade inflammation and microglial activation, 22qDS patients also show signs of dysregulated immune homeostasis with elevated plasma pro-inflammatory cytokine levels, particularly in individuals with psychosis. Microglia are brain residing immune cells that play the central role in brain development and inflammation. However, how microglial functions are impaired in 22qDS and how their dysfunction contributes to 22qDS- associated neuropsychiatric disorders remain elusive. In this study, we will comprehensively assess the impact of 22qDS on microglial function by using 22qDS patient-specific induced pluripotent stem cell (iPSC) models. We have successfully generated iPSCs from a cohort of 22qDS patients with age- and sex-matched controls (HC) and differentiated them into microglia (iMG). Our preliminary data suggest that 22qDS iMG have dysregulated mitochondrial metabolism, reduced ribosome biogenesis and display an exacerbated response to inflammatory stimulation. We hypothesize that diminished expression of genes located on 22q11.2 leads to microglial hyperactivation, partially through the miRNA dysregulation, leading to impaired neurodevelopmental and neuronal dysfunction. We will comprehensively assess the impact of 22qDS on microglial function. We will determine the molecular and cellular impacts of 22q11.2 deletions on microglia functionality and mechanistically interrogate the function of individual 22qDS genes (Aim 1). We will also assess the role of miRNA dysregulation in 22qDS microglia (Aim 2). We will further determine the impacts of 22qDS iMG on neuronal development and function by using microglia-integrated cortical organoids (Aim 3). The proposed experiments will provide important insights into the role of neuroinflammation in 22qDS and lead to identification of potential therapeutic targets that likely can inform on idiopathic SCZ as well.