Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Thomas A. Jongens
As early as 1943, reports first emerged of sex-linked transmission of intellectual disability. Several decades later, a cytogenetic variant found to segregate with intellectual impairment allowed for the localization and identification a pathogenic lesion in the fragile X mental retardation 1 (FMR1) gene. Subsequently, it was determined that loss-of-function mutations in the FMR1 gene result in the aptly named Fragile X Syndrome (FXS). The landmark discovery of FXS etiology engendered a plethora of advances in the field of intellectual disability and autism. Notably, as the most common heritable form of intellectual disability and the leading monogenetic cause of autism, FXS is an ideal genetic paradigm for the study of the cellular and molecular underpinnings of the multifarious forms of intellectual impairment and autism. Moreover, the generation of animal models of FXS has greatly facilitated progress in the field. One such model, Drosophila melanogaster, is uniquely suited to rapid genetic and biochemical approaches to probe the processes and pathways involved in FXS pathogenesis.
Recently, work from our laboratory implicated brain insulin signaling dysregulation in the development of behavioral and cognitive deficits in the Drosophila model of FXS. This finding, along with reports that FXS patients with metabolic disturbances have a higher prevalence of clinically defined autism, prompted me to explore the metabolic implications of loss of FMR1 expression. In my thesis, I uncovered striking differences in metabolism in the Drosophila model of FXS. The metabolic alterations that I revealed provide clues about the biochemical pathways that are perturbed in FXS. Further, my efforts to elucidate the mechanism underlying the observed metabolic changes precipitated the exciting discovery of a novel, clinically relevant phenotype in feeding behavior. I also uncovered new evidence that aberrant mitochondrial function and morphology are involved in FXS pathophysiology. My findings provide a solid foundation for future dissection of the precise mechanistic links between metabolism, mitochondria, and behavioral and cognitive output in the context of FXS.
Tarlow, Eliana Danice, "Investigation Of Metabolism And Mitochondrial Function In A Drosophila Model Of Fragile X Syndrome" (2017). Publicly Accessible Penn Dissertations. 2690.