The 22q11.2 microdeletion syndrome (22q11.2 DS) affects roughly 1:4000 individuals. Most common clinical manifestations include congenital heart disease, immune system dysfunction and neuropsychiatric diseases later in life. Rapid medical advances have improved the survival of affected individuals through highly specialized prenatal, neonatal and cardiac care. However, life-long neuropsychiatric morbidities remain common and a substantial challenge.
The 22q11.2 chromosomal region contains 9 genes associated with mitochondrial function. Previous studies suggest global mitochondrial dysfunction, and calcium signaling defects and neuronal hyperexcitability in neurons carrying the 22q11.2 deletion. The objective of this study is to model the brain metabolic characteristics of 22q11.2 deletion in an in vitro system.
Using human cortical spheroids (hCS) derived from human induced pluripotent stem cells (hiPSC), we study the mitochondrial characteristic and metabolic phenotype of the 22q11.2 in neuronal context. For this purpose we rely on data independent proteomic analysis. Targeted metabolomics screen and 13C based metabolic flux analysis. We couple this with functional analysis of the mitochondrial respiration using Seahorse assay, as well as to the analysis of mitochondrial properties such as membrane potential.
Our approach allowed us to verify the clinical 22q11.2 protein phenotype in our hCS system. We were further able to reveal potential targets for further investigation. Additionally we identified substantial metabolic differences in intracellular and secreted metabolites between 22q11.2 DS and controls. Functional analysis of the mitochondrial respiration using Seahorse assay and 13C based metabolic flux analysis demonstrated mitochondrial dysfunction related to ability to response to cellular stress in neurons but not neural progenitors.
We identified mitochondrial functional defects and associated metabolic imbalances in neurons carrying the 22q11.2 deletion syndrome. In ongoing studies we are investigating the mechanisms by which these newly identified phenotypes are linked to neuronal functional defects, with the overall goal of identifying targeted therapeutics.