Molecular and Genetic Analysis of Mitochondrial Phenotypes in 22q11.2 Microdeletion Syndrome, a Neurodevelopmental Disorder. 公开

Bassell, Julia Lauren (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/41687j305?locale=zh
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Abstract

Schizophrenia is a complex neuropsychiatric disorder. Due to the polygenic and heterogeneous nature of schizophrenia, we chose to focus on 22q11.2 deletion syndrome (22q11.2DS), which is the best genetic predictor of developing schizophrenia. Quantitative proteomic analysis comparing a cell line of patients with 22q11.2DS and psychosis to unaffected family members, revealed that one of most prominent organelles affected by the deletion syndrome was the mitochondria leading us to propose the following model: defects in mitochondrial function and composition caused by the 22q11.2 microdeletion syndrome lead to behavioral endophenotypes also observed in schizophrenia patients. I focused on two mitochondrial transporters: SLC25A1 (a citrate transporter) or SLC25A4 (an ADP/ATP transporter). Biochemical profiling of SLC25A1 knockout cell lines revealed decreased levels of SDHA, (succinate dehydrogenase complex subunit A) and increased levels of MRPL44 (a large subunit of the mitochondrial ribosome). This biochemical data was supported by the mitochondrial functional analysis using SeaHorse technology, which measures mitochondrial respiration. In cells deficient in SLC25A1 or SLC25A4, I found that oxygen consumption rates were significantly decreased. Since SLC25A1 and SLC25A4 deficiencies had identical functional phenotypes in the mitochondria, my prediction was that these two proteins were in the same cellular pathway. However immunoblot analysis revealed that deficiencies in expression of SLC25A1 had no impact on expression of SLC25A4. Therefore based on our current data SLC25A1 and SLC25A4 expression is affected in 22q11.2 DS, and this has a direct impact on mitochondrial respiration possibly via parallel cellular yet convergent pathways. To analyze the effect of SLC25A4 deficiencies on behavior, I utilized the model system Drosophila melanogaster and the well characterized Drosophila Activity Monitor (DAM) assay. I found that mutants of SesB (a homolog of human SLC25A4) that reduced the expression of Drosophila SLC25A4 exhibited disjointed sleep and wake cycle. This impaired sleep was recapitulated by knocking down the expression of SesB in glutamatergic neurons but not glia. Together, my data supports the hypothesis that defects in mitochondrial function that mimic 22q11.2 molecular phenotypes result in behavioral phenotypes in domains affected in patients with neuropsychiatric disorders.

Table of Contents

Introduction……………………………….……………………………………………………….8

Methods……………………………....…………………………………………………………..20

Results……………………………….………………………………………………………...…28

Discussion………………………………………………………………………………..……....36

References………………………………………………………………………………………..44

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