Thursday, May 9, 2024
5/9/2024
ABSTRACT The 22q11.2 Deletion (22qDel) is the most common microdeletion syndrome and confers a high risk for developing schizophrenia. Though the etiology of schizophrenia remains unclear, accumulating evidence supports the hypothesis that mitochondria are adversely impacted. Mitochondria are known to provide extensive support for the highly specialized and localized functions of neurons. Interestingly, several 22q11.2 locus gene products localize to mitochondria and are decreased in 22qDel. SLC25A1 and MRPL40, two of the 22q11.2 mitochondrial genes, have recently been found to interact biochemically and genetically. Therefore, 22qDel may impact neuronal development by compromising mitochondrial function. Our lab has generated isogenic 22q11.2 induced pluripotent stem cells from neurotypical controls and differentiated these lines to various 2D and 3D neuronal models. The overall objective of this project is to determine how mitochondria are impacted in 22qDel in developing neural tissue and to assess potential key putative driver genes. My central hypothesis is that the loss of 22q11.2 mitochondrial protein disrupts mitochondrial development and functionality and certain mitochondrial proteins, such as SLC25A1 and MRPL40, interacts to drive the assembly and integrity of mitochondrial ribosomal machinery and translation and are dysregulated in 22qDel. Aim 1 will quantify global mitochondrial function in live cell respiration assays and determine the protein expression of various OXPHOS subunits in developing neural cells and tissues. I will then quantify the differences in mitochondrial quantity, morphology, and membrane potential in subcellular neuronal compartments. Aim 2 will determine the impact of reduced expression of both SLC25A1 and MRPL40 on mitoribosomal integrity and expression and local/mitochondrial protein synthesis using short hairpin RNA (shRNA) in iPSC-derived neurons. These aims will inform our understanding of the impact of 22q11.2 deletion on mitochondria and neuronal development, which may provide novel insights into the shared biology of schizophrenia.
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